Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment

ABSTRACT

The present invention encompasses compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating atherosclerosis, dyslipidemias and the like. Pharmaceutical compositions and methods of use are also included.

BACKGROUND OF THE INVENTION

The present invention relates to cycloalkene compounds, theirderivatives, compositions containing such compounds and methods oftreatment or prevention in a mammal relating to dyslipidemias.Dyslipidemia is a condition wherein serum lipids are abnormal. Elevatedcholesterol and low levels of high density lipoprotein (HDL) areindependent risk factors for atherosclerosis associated with agreater-than-normal risk of atherosclerosis and cardiovascular disease.Factors known to affect serum cholesterol include geneticpredisposition, diet, body weight, degree of physical activity, age andgender. While cholesterol in normal amounts is a vital building blockfor cell membranes and essential organic molecules such as steroids andbile acids, cholesterol in excess is known to contribute tocardiovascular disease. For example, cholesterol, through itsrelationship with foam cells, is a primary component of plaque whichcollects in coronary arteries, resulting in the cardiovascular diseasetermed atherosclerosis.

Traditional therapies for reducing cholesterol include medications suchas statins (which reduce production of cholesterol by the body). Morerecently, the value of nutrition and nutritional supplements in reducingblood cholesterol has received significant attention. For example,dietary compounds such as soluble fiber, vitamin E, soy, garlic, omega-3fatty acids, and niacin have all received significant attention andresearch funding.

Niacin or nicotinic acid (pyridine-3-carboxylic acid) is a drug thatreduces coronary events in clinical trials. It is commonly known for itseffect in elevating serum levels of high density lipoproteins (HDL).Importantly, niacin also has a beneficial effect on other lipidprofiles. Specifically, it reduces low density lipoproteins (LDL), verylow density lipoproteins (VLDL), and triglycerides (TG). However, theclinical use of nicotinic acid is limited by a number of adverseside-effects including cutaneous vasodilation, sometimes calledflushing.

Despite the attention focused on traditional and alternative means forcontrolling serum cholesterol, serum triglycerides, and the like, asignificant portion of the population has total cholesterol levelsgreater than about 200 mg/dL, and are thus candidates for dyslipidemiatherapy. There thus remains a need in the art for compounds,compositions and alternative methods of reducing total cholesterol,serum triglycerides, and the like, and raising HDL.

The present invention relates to compounds that have been discovered tohave effects in modifying serum lipid levels.

The invention thus provides compositions for effecting reduction intotal cholesterol and triglyceride concentrations and raising HDL, inaccordance with the methods described.

Consequently one object of the present invention is to provide anicotinic acid receptor agonist that can be used to treat dyslipidemias,atherosclerosis, diabetes, metabolic syndrome and related conditionswhile minimizing the adverse effects that are associated with niacintreatment.

Yet another object is to provide a pharmaceutical composition for oraluse.

These and other objects will be apparent from the description providedherein.

SUMMARY OF THE INVENTION

A compound represented by formula I:

or a pharmaceutically acceptable salt or solvate thereof is disclosedwherein:

X represents CH₂, O, S, S(O), SO₂ or NH, such that when X represents NH,the nitrogen atom may be optionally substituted with R⁶, C(O)R⁶, orSO₂R⁶, wherein:

R⁶ represents C₁₋₃alkyl optionally substituted with 1-3 groups, 0-3 ofwhich are halo, and 0-1 of which are selected from the group consistingof: OC₁₋₃alkyl, OH, NH₂, NHC₁₋₃alkyl, N(C₁₋₃alkyl)₂, CN, Hetcy, Aryl andHAR,

said Aryl and HAR being further optionally substituted with 1-3 groups,1-3 of which are halo, and 0-1 of which are selected from the groupconsisting of: OH, NH₂, C₁₋₃alkyl, C₁₋₃alkoxy, haloC₁₋₃alkyl andhaloC₁₋₃alkoxy groups;

a and b are each integers 1, 2 or 3, such that the sum of a and b is 2,3 or 4;

ring A represents a 6-10 membered aryl, a 5-13 membered heteroaryl or apartially aromatic heterocyclic group, said heteroaryl and partiallyaromatic heterocyclic group containing at least one heteroatom selectedfrom O, S, S(O), S(O)₂ and N, and optionally containing 1 otherheteroatom selected from O and S, and optionally containing 1-3additional N atoms, with up to 5 heteroatoms being present;

each R² and R³ is independently H, C₁₋₃alkyl, haloC₁₋₃alkyl, OC₁₋₃alkyl,haloC₁₋₃alkoxy, OH or F;

n represents an integer of from 1 to 5;

each R⁴ is H or is independently selected from halo and R⁶;

R⁵ represents —CO₂H,

or —C(O)NHSO₂R^(e) wherein R^(e) represents C₁₋₄alkyl or phenyl, saidC₁₋₄alkyl and phenyl each being optionally substituted with 1-3 groups,1-3 of which are selected from halo and C₁₋₃alkyl, and 1-2 of which areselected from the group consisting of: OC₁₋₃alkyl, haloC₁₋₃alkyl,haloC₁₋₃alkoxy, OH, NH₂ and NHC₁₋₃alkyl;

and each R¹ is H or is independently selected from the group consistingof:

a) halo, OH, CO₂H, CN, NH₂, S(O)₀₋₂R^(e), C(O)R^(e), OC(O)R^(e) andCO₂R^(e), wherein R^(e) is as previously defined;

b) C₁₋₆ alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and alkyl portion ofOC₁₋₆alkyl being optionally substituted with 1-3 groups, 1-3 of whichare halo and 1-2 of which are selected from: OH, CO₂H, CO₂C₁₋₄alkyl,CO₂C₁₋₄haloalkyl, OCO₂C₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂, Hetcyand CN;

c) NHC₁₋₄alkyl and N(C₁₋₄alkyl)₂, the alkyl portions of which areoptionally substituted as set forth in (b) above;

d) C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂, C(O)Hetcy,C(O)NHOC₁₋₄alkyl and C(O)N(C₁₋₄alkyl)(OC₁₋₄alkyl), the alkyl portions ofwhich are optionally substituted as set forth in (b) above;

e) NR′C(O)R″, NR′SO₂R″, NR′CO₂R″ and NR′C(O)NR″R′″ wherein:

R′ represents H, C₁₋₃alkyl or haloC₁₋₃alkyl,

R″ represents (a) C₁₋₈alkyl optionally substituted with 1-4 groups, 0-4of which are halo, and 0-1 of which are selected from the groupconsisting of: OC₁₋₆alkyl, OH, CO₂H, CO₂C₁₋₄alkyl, CO₂C₁₋₄haloalkyl,NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂, CN, Hetcy, Aryl and HAR,

-   -   said Hetcy, Aryl and HAR being further optionally substituted        with 1-3 halo, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl or        haloC₁₋₄alkoxy groups;        -   (b) Hetcy, Aryl or HAR, each being optionally substituted            with 1-3 members selected from the group consisting of:            halo, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl and            haloC₁₋₄alkoxy groups;

and R′″ representing H or R″;

f) phenyl or a 5-6 membered heteroaryl or a Hetcy group attached at anyavailable ring atom and each being optionally substituted with 1-3groups, 1-3 of which are selected from halo, C₁₋₃alkyl and haloC₁₋₃alkylgroups, and 1-2 of which are selected from OC₁₋₃alkyl and haloOC₁₋₃alkylgroups, and 0-1 of which is selected from the group consisting of:

-   -   i) OH; CO₂H; CN; NH₂ and S(O)₀₋₂R^(e) wherein R^(e) is as        described above;    -   ii) NHC₁₋₄alkyl and N(C₁₋₄alkyl)₂, the alkyl portions of which        are optionally substituted with 1-3 groups, 1-3 of which are        halo and 1-2 of which are selected from: OH, CO₂H, CO₂C₁₋₄alkyl,        CO₂C₁₋₄haloalkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂ and CN;    -   iii) C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂,        C(O)NHOC₁₋₄alkyl and C(O)N(C₁₋₄alkyl)(OC₁₋₄alkyl), the alkyl        portions of which are optionally substituted as set forth in b)        above; and    -   iv) NR′C(O)R″, NR′ SO₂R″, NR′CO₂R″ and NR′C(O)NR″R′″ wherein R′,        R″ and R′″ are as described above.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl and the like, means carbon chains which may be linear,branched, or cyclic, or combinations thereof, containing the indicatednumber of carbon atoms. If no number is specified, 1-6 carbon atoms areintended for linear and 3-7 carbon atoms for branched alkyl groups.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and thelike. Cycloalkyl is a subset of alkyl; if no number of atoms isspecified, 3-7 carbon atoms are intended, forming 1-3 carbocyclic ringsthat are fused. “Cycloalkyl” also includes monocyclic rings fused to anaryl group in which the point of attachment is on the non-aromaticportion. Examples of cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,decahydronaphthyl, indanyl and the like. Haloalkoxy and haloOalkyl areused interchangeably and refer to halo substituted alkyl groups linkedthrough the oxygen atom. Haloalkyl and haloalkoxy includemono-substituted as well as multiple substituted alkyl and alkoxygroups, up to perhalo substituted alkyl and alkoxy. For example,trifluoromethyl and trifluoromethoxy are included.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Aryl” (Ar) means mono- and bicyclic aromatic rings containing 6-10carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and thelike.

“Heteroaryl” (HAR) unless otherwise specified, means mono-, bicyclic andtricyclic aromatic ring systems containing at least one heteroatomselected from O, S, S(O), SO₂ and N, with each ring containing 5 to 6atoms. HAR groups may contain from 5-14, preferably 5-13 atoms. Examplesinclude, but are not limited to, pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl,pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl,benzotriazolyl, furo(2,3-b)pyridyl, benzoxazinyl,tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, quinolyl,isoquinolyl, indolyl, dihydroindolyl, quinoxalinyl, quinazolinyl,naphthyridinyl, pteridinyl, 2,3-dihydrofuro(2,3-b)pyridyl and the like.Heteroaryl also includes aromatic carbocyclic or heterocyclic groupsfused to heterocycles that are non-aromatic or partially aromatic, andoptionally containing a carbonyl. Examples of additional heteroarylgroups include indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, and aromatic heterocyclic groups fused tocycloalkyl rings. Examples also include the following:

Heteroaryl also includes such groups in charged form, e.g., pyridinium.

“Heterocyclyl” (Hetcy) unless otherwise specified, means mono- andbicyclic saturated and partially saturated rings and ring systemscontaining at least one heteroatom selected from N, S and O, each ofsaid ring having from 3 to 10 atoms in which the point of attachment maybe carbon or nitrogen. Examples of “heterocyclyl” include, but are notlimited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,imidazolidinyl, tetrahydrofuranyl, 1,4-dioxanyl, morpholinyl,thiomorpholinyl, tetrahydrothienyl and the like. Heterocycles can alsoexist in tautomeric forms, e.g., 2- and 4-pyridones. Heterocyclesmoreover includes such moieties in charged form, e.g., piperidinium.

“Halogen” (Halo) includes fluorine, chlorine, bromine and iodine.

The phrase “in the absence of substantial flushing” refers to the sideeffect that is often seen when nicotinic acid is administered intherapeutic amounts. The flushing effect of nicotinic acid usuallybecomes less frequent and less severe as the patient develops toleranceto the drug at therapeutic doses, but the flushing effect still occursto some extent and can be transient. Thus, “in the absence ofsubstantial flushing” refers to the reduced severity of flushing when itoccurs, or fewer flushing events than would otherwise occur. Preferably,the incidence of flushing (relative to niacin) is reduced by at leastabout a third, more preferably the incidence is reduced by half, andmost preferably, the flushing incidence is reduced by about two thirdsor more. Likewise, the severity (relative to niacin) is preferablyreduced by at least about a third, more preferably by at least half, andmost preferably by at least about two thirds. Clearly a one hundredpercent reduction in flushing incidence and severity is most preferable,but is not required.

One aspect of the invention relates to a compound represented by formulaI:

or a pharmaceutically acceptable salt or solvate thereof is disclosedwherein:

X represents CH₂, O, S, S(O), SO₂ or NH, such that when X represents NH,the nitrogen atom may be optionally substituted with R⁶, C(O)R⁶, orSO₂R⁶, wherein:

R⁶ represents C₁₋₃alkyl optionally substituted with 1-3 groups, 0-3 ofwhich are halo, and 0-1 of which are selected from the group consistingof: OC₁₋₃alkyl, OH, NH₂, NHC₁₋₃alkyl, N(C₁₋₃alkyl)₂, CN, Hetcy, Aryl andHAR,

said Aryl and HAR being further optionally substituted with 1-3 groups,1-3 of which are halo, and 0-1 of which are selected from the groupconsisting of: OH, NH₂, C₁₋₃alkyl, C₁₋₃alkoxy, haloC₁₋₃alkyl andhaloC₁₋₃alkoxy groups;

a and b are each integers 1, 2 or 3, such that the sum of a and b is 2,3 or 4;

ring A represents a 6-10 membered aryl, a 5-13 membered heteroaryl or apartially aromatic heterocyclic group, said heteroaryl and partiallyaromatic heterocyclic group containing at least one heteroatom selectedfrom O, S, S(O), S(O)₂ and N, and optionally containing 1 otherheteroatom selected from O and S, and optionally containing 1-3additional N atoms, with up to 5 heteroatoms being present;

each R² and R³ is independently H, C₁₋₃alkyl, haloC₁₋₃alkyl, OC₁₋₃alkyl,haloC₁₋₃alkoxy, OH or F;

n represents an integer of from 1 to 5;

each R⁴ is H or is independently selected from halo and R⁶;

R⁵ represents —CO₂H,

or —C(O)NHSO₂R^(e) wherein R^(e) represents C₁₋₄alkyl or phenyl, saidC₁₋₄alkyl and phenyl each being optionally substituted with 1-3 groups,1-3 of which are selected from halo and C₁₋₃alkyl, and 1-2 of which areselected from the group consisting of: OC₁₋₃alkyl, haloC₁₋₃alkyl,haloC₁₋₃alkoxy, OH, NH₂ and NHC₁₋₃alkyl;

and each R¹ is H or is independently selected from the group consistingof:

a) halo, OH, CO₂H, CN, NH₂, S(O)₀₋₂R^(e), C(O)R^(e), OC(O)R^(e) andCO₂R^(e), wherein R^(e) is as previously defined;

b) C₁₋₆ alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and alkyl portion ofOC₁₋₆alkyl being optionally substituted with 1-3 groups, 1-3 of whichare halo and 1-2 of which are selected from: OH, CO₂H, CO₂C₁₋₄alkyl,CO₂C₁₋₄haloalkyl, OCO₂C₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂, Hetcyand CN;

c) NHC₁₋₄alkyl and N(C₁₋₄alkyl)₂, the alkyl portions of which areoptionally substituted as set forth in (b) above;

d) C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂, C(O)Hetcy,C(O)NHOC₁₋₄alkyl and C(O)N(C₁₋₄alkyl)(OC₁₋₄alkyl), the alkyl portions ofwhich are optionally substituted as set forth in (b) above;

e) NR′C(O)R″, NR′SO₂R″, NR′CO₂R″ and NR′C(O)NR″R′″ wherein:

R′ represents H, C₁₋₃alkyl or haloC₁₋₃alkyl,

R″ represents (a) C₁₋₈alkyl optionally substituted with 1-4 groups, 0-4of which are halo, and 0-1 of which are selected from the groupconsisting of: OC₁₋₆alkyl, OH, CO₂H, CO₂C₁₋₄alkyl, CO₂C₁₋₄haloalkyl,NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂, CN, Hetcy, Aryl and HAR,

-   -   said Hetcy, Aryl and HAR being further optionally substituted        with 1-3 halo, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl or        haloC₁₋₄alkoxy groups; or        -   (b) Hetcy, Aryl or HAR, each being optionally substituted            with 1-3 members selected from the group consisting of:            halo, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl and            haloC₁₋₄alkoxy groups;

and R′″ representing H or R″;

f) phenyl or a 5-6 membered heteroaryl or a Hetcy group attached at anyavailable ring atom and each being optionally substituted with 1-3groups, 1-3 of which are selected from halo, C₁₋₃alkyl and haloC₁₋₃alkylgroups, and 1-2 of which are selected from OC₁₋₃alkyl and haloOC₁₋₃alkylgroups, and 0-1 of which is selected from the group consisting of:

-   -   i) OH; CO₂H; CN; NH₂ and S(O)₀₋₂R^(e) wherein R^(e) is as        described above;    -   ii) NHC₁₋₄alkyl and N(C₁₋₄alkyl)₂, the alkyl portions of which        are optionally substituted with 1-3 groups, 1-3 of which are        halo and 1-2 of which are selected from: OH, CO₂H, CO₂C₁₋₄alkyl,        CO₂C₁₋₄haloalkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂ and CN;    -   iii) C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂,        C(O)NHOC₁₋₄alkyl and C(O)N(C₁₋₄alkyl)(OC₁₋₄alkyl), the alkyl        portions of which are optionally substituted as set forth in b)        above; and    -   iv) NR′C(O)R″, NR′ SO₂R″, NR′CO₂R″ and NR′C(O)NR″R′″ wherein R′,        R″ and R′″ are as described above.

One aspect of the invention that is of interest relates to a compound offormula I wherein up to 4 R² and R³ moieties are selected from the groupconsisting of: C₁₋₃alkyl, haloC₁₋₃alkyl, OC₁₋₃alkyl, haloC₁₋₃alkoxy, OHand F, and any remaining R² and R³ moieties represent H.

Another subset of compounds that is of interest relates to compounds offormula I wherein ring A is a phenyl or naphthyl group, a 5-6 memberedmonocyclic heteroaryl group or a 9-13 membered bicyclic or tricyclicheteroaryl group. Within this subset of compounds, all other variablesare as defined with respect to formula I.

More particularly, a subset of compounds that is of interest relates tocompounds of formula I wherein ring A is selected from the groupconsisting of: phenyl; naphthyl;

HAR which is a member selected from the group consisting of: pyrrolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl,thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl,triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzopyrazolyl, benzotriazolyl, furo(2,3-b)pyridyl, benzoxazinyl,tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, quinolyl,isoquinolyl, indolyl, dihydroindolyl, quinoxalinyl, quinazolinyl,naphthyridinyl, pteridinyl, 2,3-dihydrofuro(2,3-b)pyridyl indolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, or amember selected from the group consisting of:

Even more particularly, an aspect of the invention that is of interestrelates to a compound of formula I wherein ring A is selected from thegroup consisting of: phenyl; naphthyl;

HAR which is a member selected from the group consisting of: isoxazolyl,pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, thienyl,benzothiazolyl, or a member selected from the group consisting of:

Within this subset of compounds, all other variables are as defined withrespect to formula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein each R¹ is H or is selected from the group consistingof:

a) halo, OH, CN, NH₂ and S(O)₀₋₂R^(e) wherein R^(e) is methyl or phenyloptionally substituted with 1-3 halo groups;

b) C₁₋₃ alkyl and OC₁₋₃alkyl, each being optionally substituted with 1-3groups, 1-3 of which are halo and 1-2 of which are selected from: OH,NH₂, NHC₁₋₄alkyl and CN;

c) NR′ SO₂R″ and NR′C(O)NR″R′″ wherein:

R′ represents H, C₁₋₃alkyl or haloC₁₋₃alkyl,

R″ represents (a) C₁₋₈alkyl optionally substituted with 1-4 groups, 0-4of which are halo, and 0-1 of which are selected from the groupconsisting of: OC₁₋₆alkyl, OH, CO₂H, CO₂C₁₋₄alkyl, CO₂C₁₋₄haloalkyl,OCO₂C₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂, CN, Hetcy, Aryl and HAR,

-   -   said Hetcy, Aryl and HAR being further optionally substituted        with 1-3 groups selected from: halo, C₁₋₄alkyl, C₁₋₄alkoxy,        haloC₁₋₄alkyl and haloC₁₋₄alkoxy;        -   (b) Hetcy, Aryl or HAR, said Aryl and HAR being optionally            substituted with 1-3 groups selected from: halo, C₁₋₄alkyl,            C₁₋₄alkoxy, haloC₁₋₄alkyl and haloC₁₋₄alkoxy;

and R′″ representing H or R″; and

d) phenyl or a 5-6 membered heteroaryl or a heterocyclic group attachedat any available point and being optionally substituted with 1-3 groups,1-3 of which are halo, C₁₋₃alkyl or haloC₁₋₃alkyl groups, 1-2 of whichare OC₁₋₃alkyl or haloOC₁₋₃alkyl groups, and 1 of which is selected fromthe group consisting of:

-   -   i) OH; CO₂H; CN; NH₂ and S(O)₀₋₂R^(e) wherein R^(e) is as        described above;    -   ii) NHC₁₋₄alkyl, the alkyl portion of which is optionally        substituted with 1-3 groups, 1-3 of which are halo and 1 of        which is selected from: OH, CO₂H, CO₂C₁₋₄alkyl,        CO₂C₁₋₄haloalkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂ and CN;    -   iii) C(O)NH₂, C(O)NHC₁₋₄alkyl and C(O)N(C₁₋₄alkyl)₂, the alkyl        portions of which are optionally substituted as set forth in (b)        above; and    -   iv) NR′C(O)R″ and NR′ SO₂R″ wherein R′ and R″ are as described        above.        Within this subset of compounds, all other variables are as        defined with respect to formula I.

In particular, another subset of compounds that is of interest relatesto compounds of formula I wherein each R¹ is H or is selected from thegroup consisting of:

a) halo, OH, CN and NH₂;

b) C₁₋₃alkyl and OC₁₋₃alkyl, each being optionally substituted with 1-3groups, 1-3 of which are halo and 1-2 of which are selected from: OH,NH₂, NHC₁₋₄alkyl and CN;

c) phenyl or a 5-6 membered heteroaryl or a heterocyclic group attachedat any available point and being optionally substituted with 1-3 groups,1-3 of which are halo, C₁₋₃alkyl or haloC₁₋₃alkyl groups, 1-2 of whichare OC₁₋₃alkyl or haloOC₁₋₃alkyl groups, and 1 of which is selected fromthe group consisting of:

-   -   i) OH, CN and NH₂. Within this subset of compounds, all other        variables are as defined with respect to formula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein a and b are 1 or 2 such that the sum of a and b is 2or 3. Within this subset of compounds, all other variables are asdefined with respect to formula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein X represents O, S, N or CH₂. Within this subset ofcompounds, all other variables are as defined with respect to formula I.

More particularly, another subset of compounds that is of interestrelates to compounds of formula I wherein X represents O or CH₂. Withinthis subset of compounds, all other variables are as defined withrespect to formula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein R² and R³ are independently H, C₁₋₃alkyl, OH orhaloC₁₋₃alkyl. Within this subset of compounds, all other variables areas defined with respect to formula I.

More particularly, another subset of compounds that is of interestrelates to compounds of formula I wherein R² and R³ are independently H,C₁₋₃alkyl or haloC₁₋₃alkyl. Within this subset of compounds, all othervariables are as defined with respect to formula I.

More particularly, a subset of compounds that is of interest relates tocompounds of formula I wherein R² and R³ are independently H or methyl.Within this subset of compounds, all other variables are as defined withrespect to formula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein n represents an integer of from 2 to 4. Within thissubset of compounds, all other variables are as defined with respect toformula I.

More particularly, a subset of compounds that is of interest relates tocompounds of formula I wherein n is 2. Within this subset of compounds,all other variables are as defined with respect to formula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein each R⁴ is H or is independently selected from thegroup consisting of: halo, C₁₋₃alkyl optionally substituted with 1-3halo groups and 0-1 OC₁₋₃alkyl groups. Within this subset of compounds,all other variables are as defined with respect to formula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein each R⁴ is H or is independently selected from halo orC₁₋₃alkyl optionally substituted with 1-3 halo groups. Within thissubset of compounds, all other variables are as defined with respect toformula I.

Another subset of compounds that is of interest relates to compounds offormula I wherein R⁵ represents —CO₂H. Within this subset of compounds,all other variables are as defined with respect to formula I.

A particular subset of compounds that is of interest relates tocompounds of formula I or a pharmaceutically acceptable salt or solvatethereof wherein:

ring A is a phenyl or naphthyl group, a 5-6 membered monocyclicheteroaryl group or a 9-13 membered bicyclic or tricyclic heteroarylgroup;

each R¹ is H or is selected from the group consisting of:

a) halo, OH, CN, NH₂ and S(O)₀₋₂R^(e) wherein R^(e) is methyl or phenyloptionally substituted with 1-3 halo groups;

b) C₁₋₃ alkyl and OC₁₋₃alkyl, each being optionally substituted with 1-3groups, 1-3 of which are halo and 1-2 of which are selected from: OH,NH₂, NHC₁₋₄alkyl and CN;

c) NR′ SO₂R″ and NR′C(O)NR″R′″ wherein:

R′ represents H, C₁₋₃alkyl or haloC₁₋₃alkyl,

R″ represents (a) C₁₋₈alkyl optionally substituted with 1-4 groups, 0-4of which are halo, and 0-1 of which are selected from the groupconsisting of: OC₁₋₆alkyl, OH, CO₂H, CO₂C₁₋₄alkyl, CO₂C₁₋₄haloalkyl,OCO₂C₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂, CN, Hetcy, Aryl and HAR,

-   -   said Hetcy, Aryl and HAR being further optionally substituted        with 1-3 halo, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl and        haloC₁₋₄alkoxy groups;        -   (b) Hetcy, Aryl or HAR, said Aryl and HAR being further            optionally substituted with 1-3 halo, C₁₋₄alkyl, C₁₋₄alkoxy,            haloC₁₋₄alkyl and haloC₁₋₄alkoxy groups;

and R′″ representing H or R″; and

d) phenyl or a 5-6 membered heteroaryl or a heterocyclic group attachedat any available point and being optionally substituted with 1-3 groups,1-3 of which are halo, C₁₋₃alkyl or haloC₁₋₃alkyl groups, 1-2 of whichare OC₁₋₃alkyl or haloOC₁₋₃alkyl groups, and 1 of which is selected fromthe group consisting of:

-   -   i) OH; CO₂H; CN; NH₂; S(O)₀₋₂R^(e) wherein R^(e) is as described        above;    -   ii) NHC₁₋₄alkyl the alkyl portion of which is optionally        substituted with 1-3 groups, 1-3 of which are halo and 1 of        which is selected from: OH, CO₂H, CO₂C₁₋₄alkyl,        CO₂C₁₋₄haloalkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂ and CN;    -   iii) C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂, the alkyl        portions of which are optionally substituted as set forth in (b)        above; and    -   iv) NR′C(O)R″ and NR′ SO₂R″ wherein R′ and R″ are as described        above;

a and b are 1 or 2 such that the sum of a and b is 2 or 3;

X represents O or CH₂;

R² and R³ are independently H, OH, C₁₋₃alkyl or haloC₁₋₃alkyl;

n represents 2;

R⁴ is H or is independently selected from the group consisting of: halo,C₁₋₃alkyl optionally substituted with 1-3 halo groups or 0-1 OC₁₋₃alkylgroups; and

R⁵ represents —CO₂H.

A more particular subset of compounds that is of interest relates tocompounds of formula I or a pharmaceutically acceptable salt of solvatethereof wherein:

ring A is selected from the group consisting of:

each R¹ is independently H, CH₃, phenyl, 4-hydroxy-phenyl, OH,2-hydroxy-phenyl, 3-hydroxy-phenyl, 3-amino-phenyl,2,3-dihydro-benzofuran-6-yl, 2-chloro-4-hydroxy-phenyl, 1H-pyrazol-4-yl,5-hydroxy-pyridin-2-yl, 4-hydroxy-pyrazol-1-yl, 1H-[1,2,3]triazol-4-yl,or 5-fluoro-pyridin-2-yl;

a and b are 1 or 2 such that the sum of a and b is 2 or 3;

X represents CH₂;

each R² and R³ is independently H, OH or CH₃;

n represents 2;

R⁴ is H, CH₃, CH₂CH₃, CF₃ or CH₂OCH₃; and

R⁵ represents —CO₂H.

Representative examples of species that are of interest are shown belowin Table I. Within this subset of compounds, all other variables are asoriginally defined with respect to formula I.

TABLE 1

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

Compound 41

Pharmaceutically acceptable salts and solvates thereof are included aswell.

Many of the compounds of formula I contain asymmetric centers and canthus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms are included.

Moreover, chiral compounds possessing one stereocenter of generalformula I, may be resolved into their enantiomers in the presence of achiral environment using methods known to those skilled in the art.Chiral compounds possessing more than one stereocenter may be separatedinto their diastereomers in an achiral environment on the basis of theirphysical properties using methods known to those skilled in the art.Single diastereomers that are obtained in racemic form may be resolvedinto their enantiomers as described above.

If desired, racemic mixtures of compounds may be separated so thatindividual enantiomers are isolated. The separation can be carried outby methods well known in the art, such as the coupling of a racemicmixture of compounds of Formula I to an enantiomerically pure compoundto form a diastereomeric mixture, which is then separated intoindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediasteromeric derivatives may then be converted to substantially pureenantiomers by cleaving the added chiral residue from the diastereomericcompound.

The racemic mixture of the compounds of Formula I can also be separateddirectly by chromatographic methods utilizing chiral stationary phases,which methods are well known in the art.

Alternatively, enantiomers of compounds of the general Formula I may beobtained by stereoselective synthesis using optically pure startingmaterials or reagents.

Some of the compounds described herein exist as tautomers, which havedifferent points of attachment for hydrogen accompanied by one or moredouble bond shifts. For example, a ketone and its enol form areketo-enol tautomers. Or for example, a 2-hydroxyquinoline can reside inthe tautomeric 2-quinolone form. The individual tautomers as well asmixtures thereof are included.

Dosing Information

The dosages of compounds of formula I or a pharmaceutically acceptablesalt or solvate thereof vary within wide limits. The specific dosageregimen and levels for any particular patient will depend upon a varietyof factors including the age, body weight, general health, sex, diet,time of administration, route of administration, rate of excretion, drugcombination and the severity of the patient's condition. Considerationof these factors is well within the purview of the ordinarily skilledclinician for the purpose of determining the therapeutically effectiveor prophylactically effective dosage amount needed to prevent, counter,or arrest the progress of the condition. Generally, the compounds willbe administered in amounts ranging from as low as about 0.01 mg/day toas high as about 2000 mg/day, in single or divided doses. Arepresentative dosage is about 0.1 mg/day to about 1 g/day. Lowerdosages can be used initially, and dosages increased to further minimizeany untoward effects. It is expected that the compounds described hereinwill be administered on a daily basis for a length of time appropriateto treat or prevent the medical condition relevant to the patient,including a course of therapy lasting months, years or the life of thepatient.

Combination Therapy

One or more additional active agents may be administered with thecompounds described herein. The additional active agent or agents can belipid modifying compounds or agents having other pharmaceuticalactivities, or agents that have both lipid-modifying effects and otherpharmaceutical activities. Examples of additional active agents whichmay be employed include but are not limited to HMG-CoA reductaseinhibitors, which include statins in their lactonized or dihydroxy openacid forms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767),simvastatin (see U.S. Pat. No. 4,444,784), dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof,pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227), fluvastatin particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772), atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995), pitavastatin also referred to as NK-104(see PCT international publication number WO 97/23200) and rosuvastatin,also known as CRESTOR®; see U.S. Pat. No. 5,260,440); HMG-CoA synthaseinhibitors; squalene epoxidase inhibitors; squalene synthetaseinhibitors (also known as squalene synthase inhibitors), acyl-coenzymeA: cholesterol acyltransferase (ACAT) inhibitors including selectiveinhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors of ACAT-1 and-2; microsomal triglyceride transfer protein (MTP) inhibitors;endothelial lipase inhibitors; bile acid sequestrants; LDL receptorinducers; platelet aggregation inhibitors, for example glycoproteinIIb/IIIa fibrinogen receptor antagonists and aspirin; human peroxisomeproliferator activated receptor gamma (PPAR-gamma) agonists includingthe compounds commonly referred to as glitazones for examplepioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidine diones as well asthose PPAR-gamma agonists outside the thiazolidine dione structuralclass; PPAR-alpha agonists such as clofibrate, fenofibrate includingmicronized fenofibrate, and gemfibrozil; PPAR dual alpha/gamma agonists;vitamin B₆ (also known as pyridoxine) and the pharmaceuticallyacceptable salts thereof such as the HCl salt; vitamin B₁₂ (also knownas cyanocobalamin); folic acid or a pharmaceutically acceptable salt orester thereof such as the sodium salt and the methylglucamine salt;anti-oxidant vitamins such as vitamin C and E and beta carotene;beta-blockers; angiotensin II antagonists such as losartan; angiotensinconverting enzyme inhibitors such as enalapril and captopril; renininhibitors, calcium channel blockers such as nifedipine and diltiazem;endothelin antagonists; agents that enhance ABCA1 gene expression;cholesteryl ester transfer protein (CETP) inhibiting compounds,5-lipoxygenase activating protein (FLAP) inhibiting compounds,5-lipoxygenase (5-LO) inhibiting compounds, farnesoid X receptor (FXR)ligands including both antagonists and agonists; Liver X Receptor(LXR)-alpha ligands, LXR-beta ligands, bisphosphonate compounds such asalendronate sodium; cyclooxygenase-2 inhibitors such as rofecoxib andcelecoxib; and compounds that attenuate vascular inflammation.

Cholesterol absorption inhibitors can also be used in the presentinvention. Such compounds block the movement of cholesterol from theintestinal lumen into enterocytes of the small intestinal wall, thusreducing serum cholesterol levels. Examples of cholesterol absorptioninhibitors are described in U.S. Pat. Nos. 5,846,966, 5,631,365,5,767,115, 6,133,001, 5,886,171, 5,856,473, 5,756,470, 5,739,321,5,919,672, and in PCT application Nos. WO 00/63703, WO 00/60107, WO00/38725, WO 00/34240, WO 00/20623, WO 97/45406, WO 97/16424, WO97/16455, and WO 95/08532. The most notable cholesterol absorptioninhibitor is ezetimibe, also known as1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,described in U.S. Pat. Nos. 5,767,115 and 5,846,966.

Therapeutically effective amounts of cholesterol absorption inhibitorsinclude dosages of from about 0.01 mg/kg to about 30 mg/kg of bodyweight per day, preferably about 0.1 mg/kg to about 15 mg/kg.

For diabetic patients, the compounds used in the present invention canbe administered with conventional diabetic medications. For example, adiabetic patient receiving treatment as described herein may also betaking insulin or an oral antidiabetic medication. One example of anoral antidiabetic medication useful herein is metformin.

In the event that these niacin receptor agonists induce some degree ofvasodilation, it is understood that the compounds of formula I may beco-dosed with a vasodilation suppressing agent. Consequently, one aspectof the methods described herein relates to the use of a compound offormula I or a pharmaceutically acceptable salt or solvate thereof incombination with a compound that reduces flushing. Conventionalcompounds such as aspirin, ibuprofen, naproxen, indomethacin, otherNSAIDs, COX-2 selective inhibitors and the like are useful in thisregard, at conventional doses. Alternatively, DP antagonists are usefulas well. Doses of the DP receptor antagonist and selectivity are suchthat the DP antagonist selectively modulates the DP receptor withoutsubstantially modulating the CRTH2 receptor. In particular, the DPreceptor antagonist ideally has an affinity at the DP receptor (i.e.,K_(i)) that is at least about 10 times higher (a numerically lower K_(i)value) than the affinity at the CRTH2 receptor. Any compound thatselectively interacts with DP according to these guidelines is deemed“DP selective”. This is in accordance with US Published Application No.2004/0229844A1 published on Nov. 18, 2004, incorporated herein byreference.

Dosages for DP antagonists as described herein, that are useful forreducing or preventing the flushing effect in mammalian patients,particularly humans, include dosages ranging from as low as about 0.01mg/day to as high as about 100 mg/day, administered in single or divideddaily doses. Preferably the dosages are from about 0.1 mg/day to as highas about 1.0 g/day, in single or divided daily doses.

Examples of compounds that are particularly useful for selectivelyantagonizing DP receptors and suppressing the flushing effect includethe following:

as well as the pharmaceutically acceptable salts and solvates thereof.

The compound of formula I or a pharmaceutically acceptable salt orsolvate thereof and the DP antagonist can be administered together orsequentially in single or multiple daily doses, e.g., bid, tid or qid,without departing from the invention. If sustained release is desired,such as a sustained release product showing a release profile thatextends beyond 24 hours, dosages may be administered every other day.However, single daily doses are preferred. Likewise, morning or eveningdosages can be utilized.

Salts and Solvates

Salts and solvates of the compounds of formula I are also included inthe present invention, and numerous pharmaceutically acceptable saltsand solvates of nicotinic acid are useful in this regard. Alkali metalsalts, in particular, sodium and potassium, form salts that are usefulas described herein. Likewise alkaline earth metals, in particular,calcium and magnesium, form salts that are useful as described herein.Various salts of amines, such as ammonium and substituted ammoniumcompounds also form salts that are useful as described herein.Similarly, solvated forms of the compounds of formula I are usefulwithin the present invention. Examples include the hemihydrate, mono-,di-, tri- and sesquihydrate.

The compounds of the invention also include esters that arepharmaceutically acceptable, as well as those that are metabolicallylabile. Metabolically labile esters include C₁₋₄ alkyl esters,preferably the ethyl ester. Many prodrug strategies are known to thoseskilled in the art. One such strategy involves engineered amino acidanhydrides possessing pendant nucleophiles, such as lysine, which cancyclize upon themselves, liberating the free acid. Similarly,acetone-ketal diesters, which can break down to acetone, an acid and theactive acid, can be used.

The compounds used in the present invention can be administered via anyconventional route of administration. The preferred route ofadministration is oral.

Pharmaceutical Compositions

The pharmaceutical compositions described herein are generally comprisedof a compound of formula I or a pharmaceutically acceptable salt orsolvate thereof, in combination with a pharmaceutically acceptablecarrier.

Examples of suitable oral compositions include tablets, capsules,troches, lozenges, suspensions, dispersible powders or granules,emulsions, syrups and elixirs. Examples of carrier ingredients includediluents, binders, disintegrants, lubricants, sweeteners, flavors,colorants, preservatives, and the like. Examples of diluents include,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate and sodium phosphate. Examples of granulating anddisintegrants include corn starch and alginic acid. Examples of bindingagents include starch, gelatin and acacia. Examples of lubricantsinclude magnesium stearate, calcium stearate, stearic acid and talc. Thetablets may be uncoated or coated by known techniques. Such coatings maydelay disintegration and thus, absorption in the gastrointestinal tractand thereby provide a sustained action over a longer period.

One embodiment of the invention that is of interest is a tablet orcapsule that is comprised of a compound of formula I or apharmaceutically acceptable salt or solvate thereof in an amount rangingfrom about 0.1 mg to about 1000 mg, in combination with apharmaceutically acceptable carrier.

In another embodiment of the invention, a compound of formula I or apharmaceutically acceptable salt or solvate thereof is combined withanother therapeutic agent and the carrier to form a fixed combinationproduct. This fixed combination product may be a tablet or capsule fororal use.

More particularly, in another embodiment of the invention, a compound offormula I or a pharmaceutically acceptable salt or solvate thereof(about 0.1 to about 1000 mg) and the second therapeutic agent (about 0.1to about 500 mg) are combined with the pharmaceutically acceptablecarrier, providing a tablet or capsule for oral use.

Sustained release over a longer period of time may be particularlyimportant in the formulation. A time delay material such as glycerylmonostearate or glyceryl distearate may be employed. The dosage form mayalso be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tabletsfor controlled release.

Other controlled release technologies are also available and areincluded herein. Typical ingredients that are useful to slow the releaseof nicotinic acid in sustained release tablets include variouscellulosic compounds, such as methylcellulose, ethylcellulose,propylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, microcrystalline cellulose, starch and thelike. Various natural and synthetic materials are also of use insustained release formulations. Examples include alginic acid andvarious alginates, polyvinyl pyrrolidone, tragacanth, locust bean gum,guar gum, gelatin, various long chain alcohols, such as cetyl alcoholand beeswax.

Optionally and of even more interest is a tablet as described above,comprised of a compound of formula I or a pharmaceutically acceptablesalt or solvate thereof, and further containing an HMG Co-A reductaseinhibitor, such as simvastatin or atorvastatin. This particularembodiment optionally contains the DP antagonist as well.

Typical release time frames for sustained release tablets in accordancewith the present invention range from about 1 to as long as about 48hours, preferably about 4 to about 24 hours, and more preferably about 8to about 16 hours.

Hard gelatin capsules constitute another solid dosage form for oral use.Such capsules similarly include the active ingredients mixed withcarrier materials as described above. Soft gelatin capsules include theactive ingredients mixed with water-miscible solvents such as propyleneglycol, PEG and ethanol, or an oil such as peanut oil, liquid paraffinor olive oil.

Aqueous suspensions are also contemplated as containing the activematerial in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients include suspending agents, forexample sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,tragacanth and acacia; dispersing or wetting agents, e.g., lecithin;preservatives, e.g., ethyl, or n-propyl para-hydroxybenzoate, colorants,flavors, sweeteners and the like.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredients inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Syrups and elixirs may also be formulated.

More particularly, a pharmaceutical composition that is of interest is asustained release tablet that is comprised of a compound of formula I ora pharmaceutically acceptable salt or solvate thereof, and a DP receptorantagonist that is selected from the group consisting of compounds Athrough AJ in combination with a pharmaceutically acceptable carrier.

Yet another pharmaceutical composition that is of more interest iscomprised of a compound of formula I or a pharmaceutically acceptablesalt or solvate thereof and a DP antagonist compound selected from thegroup consisting of compounds A, B, D, E, X, AA, AF, AG, AH, AI and AJ,in combination with a pharmaceutically acceptable carrier.

Yet another pharmaceutical composition that is of more particularinterest relates to a sustained release tablet that is comprised of acompound of formula I or a pharmaceutically acceptable salt or solvatethereof, a DP receptor antagonist selected from the group consisting ofcompounds A, B, D, E, X, AA, AF, AG, AH, AI and AJ, and simvastatin oratorvastatin in combination with a pharmaceutically acceptable carrier.

The term “composition”, in addition to encompassing the pharmaceuticalcompositions described above, also encompasses any product whichresults, directly or indirectly, from the combination, complexation oraggregation of any two or more of the ingredients, active or excipient,or from dissociation of one or more of the ingredients, or from othertypes of reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical composition of the present inventionencompasses any composition made by admixing or otherwise combining thecompounds, any additional active ingredient(s), and the pharmaceuticallyacceptable excipients.

Another aspect of the invention relates to the use of a compound offormula I or a pharmaceutically acceptable salt or solvate thereof and aDP antagonist in the manufacture of a medicament. This medicament hasthe uses described herein.

More particularly, another aspect of the invention relates to the use ofa compound of formula I or a pharmaceutically acceptable salt or solvatethereof, a DP antagonist and an HMG Co-A reductase inhibitor, such assimvastatin, in the manufacture of a medicament. This medicament has theuses described herein.

Compounds of the present invention have anti-hyperlipidemic activity,causing reductions in LDL-C, triglycerides, lipoprotein (a), free fattyacids and total cholesterol, and increases in HDL-C. Consequently, thecompounds of the present invention are useful in treating dyslipidemias.The present invention thus relates to the treatment, prevention orreversal of atherosclerosis and the other diseases and conditionsdescribed herein, by administering a compound of formula I or apharmaceutically acceptable salt or solvate in an amount that iseffective for treating, preventing or reversing said condition. This isachieved in humans by administering a compound of formula I or apharmaceutically acceptable salt or solvate thereof in an amount that iseffective to treat or prevent said condition, while preventing, reducingor minimizing flushing effects in terms of frequency and/or severity.

One aspect of the invention that is of interest relates to a compound inaccordance with formula I or a pharmaceutically acceptable salt orsolvate thereof for use in a method of treatment of the human or animalbody by therapy.

Another aspect of the invention that is of interest relates to acompound in accordance with formula I or a pharmaceutically acceptablesalt or solvate thereof for use in a method for the treatment ofatherosclerosis, dyslipidemia, diabetes, metabolic syndrome or a relatedcondition in the human or animal body by therapy.

More particularly, an aspect of the invention that is of interest is amethod of treating atherosclerosis in a human patient in need of suchtreatment comprising administering to the patient a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof in an amountthat is effective for treating atherosclerosis in the absence ofsubstantial flushing.

Another aspect of the invention that is of interest relates to a methodof raising serum HDL levels in a human patient in need of suchtreatment, comprising administering to the patient a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof in an amountthat is effective for raising serum HDL levels.

Another aspect of the invention that is of interest relates to a methodof treating dyslipidemia in a human patient in need of such treatmentcomprising administering to the patient a compound of formula I or apharmaceutically acceptable salt or solvate thereof in an amount that iseffective for treating dyslipidemia.

Another aspect of the invention that is of interest relates to a methodof reducing serum VLDL or LDL levels in a human patient in need of suchtreatment, comprising administering to the patient a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof in an amountthat is effective for reducing serum VLDL or LDL levels in the patientin the absence of substantial flushing.

Another aspect of the invention that is of interest relates to a methodof reducing serum triglyceride levels in a human patient in need of suchtreatment, comprising administering to the patient a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof in an amountthat is effective for reducing serum triglyceride levels.

Another aspect of the invention that is of interest relates to a methodof reducing serum Lp(a) levels in a human patient in need of suchtreatment, comprising administering to the patient a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof in an amountthat is effective for reducing serum Lp(a) levels. As used herein Lp(a)refers to lipoprotein (a).

Another aspect of the invention that is of interest relates to a methodof treating diabetes, and in particular, type 2 diabetes, in a humanpatient in need of such treatment comprising administering to thepatient a compound of formula I or a pharmaceutically acceptable salt orsolvate thereof in an amount that is effective for treating diabetes.

Another aspect of the invention that is of interest relates to a methodof treating metabolic syndrome in a human patient in need of suchtreatment comprising administering to the patient a compound of formulaI or a pharmaceutically acceptable salt or solvate thereof in an amountthat is effective for treating metabolic syndrome.

Another aspect of the invention that is of particular interest relatesto a method of treating atherosclerosis, dyslipidemias, diabetes,metabolic syndrome or a related condition in a human patient in need ofsuch treatment, comprising administering to the patient a compound offormula I or a pharmaceutically acceptable salt or solvate thereof and aDP receptor antagonist, said combination being administered in an amountthat is effective to treat atherosclerosis, dyslipidemia, diabetes or arelated condition in the absence of substantial flushing.

Another aspect of the invention that is of particular interest relatesto the methods described above wherein the DP receptor antagonist isselected from the group consisting of compounds A through AJ and thepharmaceutically acceptable salts and solvates thereof.

Methods of Synthesis for Compounds of Formula I

Compounds of Formula I have been prepared by the followingrepresentative reaction schemes. It is understood that similar reagents,conditions or other synthetic approaches to these structure classes areconceivable to one skilled in the art of organic synthesis. Thereforethese reaction schemes should not be construed as limiting the scope ofthe invention. All substituents are as defined above unless indicatedotherwise.

Compounds of Formula I, where X represents CH₂, a and b equal 1 andRCOOH represents:

can be prepared as illustrated in Scheme 1 by treatment of commerciallyavailable methyl 2-oxocyclopentane-1-carboxylate 1 with ammonium acetatein a polar solvent such a methanol or ethanol to give the methyl 2-aminocyclopent-1-ene-1-carboxylate 2. The amine 2 can be coupled with theappropriate acid in the presence of methanesulfonyl chloride (MsCl) andDMAP to give the desired amide 3. Finally, the ester can be saponifiedby one skilled in the art using such methods as NaOH or LiOH-dioxane togive compounds with the structure 4.

Compounds of Formula I, where X represents CH₂, a represents 2, and brepresents 1 such that the sum of a and b is 3, can be prepared asillustrated in Scheme 2 by coupling commercially available methyl orethyl 2-amino-cyclo-hex-1-ene-1-carboxylate 5 or 6 with the appropriateacid in the presence of methanesulfonyl chloride and DMAP to give thedesired amide 7. The ester can be saponified to the desired compound 8by methods known to those skilled in the art.

Shown in Scheme 3 is the preparation of acid of the structure 10 fromcommercially available material 9 by methods known to one skilled in theart, such as hydrogenation in a polar solvent, such as methanol orethanol, using Pd/C as a catalyst.

Compounds with the structure 19 can be prepared by the chemistryoutlined in Scheme 4. Thus, 6-methoxy-2-naphthaldehyde 11 can be treatedwith a suitable ylide such as(tert-Butoxycarbonyl-methylene)triphenyl-phospharane in a non-polarsolvent such as toluene or xylenes under refluxing conditions to givethe desired olefin 12. Hydrogenation of the double bond can beaccomplished using standard conditions such as H₂ (g), Pd/C in asuitable polar solvent like methanol or ethanol to give 13. Removal ofthe methyl group in the methoxynaphthyl moiety can be accomplished withboron tribromide at low temperature, followed by a careful quenching ofthe reaction with methanol to give the trans-esterified product 14.Saponification of the ester was accomplished using conditions describedearlier. The naphthol can be protected as the TBS ether using TBSOTf orTBS—Cl in the presence of a suitable base such as triethylamine orimidazole in dichloromethane. The TBS ester can be hydrolyzed with amild acid such as acetic acid in THF—H₂O to give the desired acid 17.This acid can be coupled to the methyl or ethyl2-aminocyclo-hex-1-ene-1-carboxylate in the presence of methanesulfonylchloride and DMAP to give the desired amide 18. Finally, TBS etherremoval and methyl ester saponification can be achieved usingNaOH/THF—H₂O providing compounds of the structure 19.

Compounds with the structure 28 can be prepared by the chemistryoutlined in Scheme 5. Thus, treating a suitable tetralone such as 20with LDA at low temperature followed by the addition of a suitableacylating agent such as 4-chloro-4-oxobutyrate provides the desireddiketo-ester 21. The ester can be saponified using standard conditionsknown to one skilled in the art to give the acid 22. The di-ketone 22can be converted to the fused isoxazole of the structure 23 by refluxingwith hydroxylamine hydrochloride in the presence of a base such astriethylamine in an alcoholic solvent such as methanol or ethanol.De-protection of the methyl ether can be done with boron tribromide in asuitable solvent such as dichloromethane to give the desired alcohol 24.Treatment of the intermediate 24 with a silylating agent such as TBS—Clin the presence of a base such as imidazole or triethylamine in achlorinated solvent like DCM gives the bis-silyl protected ester 25. Thesilyl ester 25 can be treated with oxalyl chloride in a solvent such asDCM under anhydrous conditions followed by coupling with methyl2-aminocyclo-pent-1-ene-1-carboxylate to give the desired amide 26. TheTBS group can be removed using aqueous TBAF. Finally, the methyl estercan be saponified using standard conditions to give compounds of thestructure 28.

Scheme 6 outlines the strategy used to synthesize compounds of thestructure 32. Coupling commercially available methyl or ethyl2-aminocyclo-hex-1-ene-1-carboxylate 5 or 6 with 3-(3-bromophenyl)propionic acid 29 in the presence of methanesulfonyl chloride and DMAPgives the desired amide 30. The bromide 30 can be converted to 31 via aSuzuki reaction with a suitable boronic acid such as 4-hydroxy phenylboronic acid in the presence of a catalyst such asBis-tert-butyl-ferrocene palladium dichloride. The ester can besaponified by methods known to those skilled in the art providingcompounds of the structure 32.

Scheme 7 outlines the strategy used to synthesize compounds of thestructure 37. Homologating aldehyde 33, followed by reduction provides34 which may be resolved into its enantiomers via chiral HPLC. Oneenantiomer is shown in Scheme 7 for illustrative purposes. Hydrolysis ofthe ethyl esters provides the acid 35, followed by demethylation andsilylation to give 36. This intermediate can be acylated with thecyclopentene fragment, and saponified to provide biaryl products such as37.

Scheme 8 outlines the strategy used to synthesize compounds of thestructure 43. The aminobenzothiazole 38 may be N-alkylated and cyclizedto form intermediate 39. The ester can be reduced to the aldehyde, andhomologated to the enoate 40. This intermediate can then be reduced andsaponified to provide the acid 41. Demethylation and silylation affordsintermediate 42, which can be acylated and saponified once again as inScheme 7 above, to provide products such as 43.

Scheme 9 outlines the strategy used to synthesize compounds of thestructure 50. Adiponitrile can be converted to the amino-nitrile 45 viaa Thorpe-Ziegler reaction using a suitable base such as LDA in a solventsuch as THF. Coupling the amino nitrile 45 to 3-(4-bromophenyl)propionic acid 46 in the presence of methanesulfonyl chloride and DMAPgives the desired amide 47. The bromide 47 can be converted to 49 via aSuzuki reaction with a suitable boronic acid such as phenyl boronic acidin the presence of a catalyst such as 1,1bis(di-tert-butylphosphino)-ferrocene palladium dichloride. Finally,treatment of the nitrile 49 with NaN₃ in the presence of a Lewis acidsuch as zinc bromide, in a suitable solvent mixture such asdioxane-water gives tetrazoles such as 50.

Scheme 10 outlines the strategy used to synthesize compounds of thestructure 54. The heterocyclic bromo aldehyde 51 can be homologated tothe intermediate 52 via several transformations including thedisplacement of an activated bromide with a malonate anion. The bromide52 can be arylated and demethylated to provide acid 53, which in turnmay be acylated and deprotected to provide compounds such as 54.

Scheme 11 displays a method for generating compounds of the structure55. The acid intermediate 52 from Scheme 10 above may be acylated, thebromide coupled with a heterocyclic boronate ester, and thisintermediate deprotected to provide compounds such as 55.

Scheme 12 demonstrates a synthetic strategy to access compounds of thestructure 59. Starting from a pyridyl bromo nitrile such as 56, thebromide may be displaced, the nitrile transformed to an N-hydroxyamidine, this intermediate acylated and then cyclized to provide theintermediate 57. Saponification of 57 can give acid 58, which may beacylated, and after deprotection provide compounds such as 59.

Scheme 13 outlines the strategy used to synthesize compounds of thestructure 63. The pyrazole 60 may be N-arylated, this intermediatehomologated to nitro 61, which in turn may be transformed to hydroxyacid 62. Upon acylation and deprotection, compounds such as 63 may beobtained.

Scheme 14 displays a method to access compounds of the structure 66. Theintermediate 64 generated in Scheme 12, may be elaborated into 65 via anintermediate oxime cycloaddition with an alkyne. The hydroxy acid 65 canbe protected, acylated and deprotected to provide compounds such as 66.

Scheme 15 shows a synthetic route used to generate compounds of thestructure 68. The intermediate 67 may be accessed from an oxidativecleavage of the requisite olefin. This alpha-methyl acid 67 may then becondensed with an N-hydroxy amidine, and this intermediate elaboratedinto compounds such as 68 using methods illustrated in the Schemesabove.

Scheme 16 outlines the strategy used to synthesize compounds of thestructure 70. This methodology follows closely to that illustrated inScheme 15 above, where intermediate 69 can now be doubly deprotected inone step to provide compounds such as 70, containing a methyl groupalpha to the amide moiety.

Scheme 17 displays methodology to synthesize compounds of the structure74. An amino heterocycle such as 71 can be converted to its halide anddisplaced with a nitrogen anionic heterocycle, followed by hydroxylintroduction to provide intermediate 72. This ester 72 may behomologated to 73, and upon acylation and protecting group manipulation,converted to compounds such as 74.

Scheme 18 displays a method for generating compounds of the structure77. The intermediate 75 can be accessed from 4-methoxyaniline viadipolar cycloaddition, and then homologated into 76. Following some ofthe methods illustrated in the Schemes above, 76 can be converted intocompounds such as 77.

Scheme 19 displays a method to access compounds of the structure 80.Alkyne 78 may be homologated and undergo a cycloaddition reaction togenerate intermediate 79. The enoate 79 may then be converted intocompounds such as 80 using methods illustrated in the Schemes above.

Scheme 20 illustrates a strategy used to synthesize compounds of thestructure 83. Malic acid 81 can be orthogonally protected, condensedwith an N-hydroxy amidine, and deprotected to generate 82. Thebis-hydroxyacid 82 may be globally silylated, and then acylated anddeprotected to provide alpha-hydroxy compounds such as 83.

Scheme 21 displays a strategy used to generate compounds of thestructure 86. Orthogonally protected acid ester intermediate 84 can beobtained via oxidative degradation of the requisite olefinic startingmaterial. The acid 84 may then be condensed with an N-hydroxy amidine,and manipulated to provide a primary carboxamide 85. A primarycarboxamide intermediate such as 85 may undergo a coupling reaction withan enol triflate, and upon further deprotection reactions, providegeminal dimethyl compounds such as 86.

Scheme 22 outlines a methodology to access compounds of the structure88. Commercially available (S)-pulegone can be converted intointermediate 87 via reverse aldol, acylation with Mander's reagent, andenamine formation. Using a similar alpha-methyl ester intermediateillustrated in Scheme 16, chiral amine 87 may be elaborated intocompounds such as 88.

Scheme 23 displays a strategy to access compounds of the structure 89.Commercially available symmetrical ketones, such as4-ethylcyclohexanone, can be acylated with Mander's reagent, followed byenol triflate formation with Comins' reagent. Using similar metalcatalyzed coupling methodology illustrated in Scheme 21, differentregioisomerically substituted cyclohexene compounds such as 89 may beaccessed.

Scheme 24 illustrates a methodology to access compounds of the structure90. Commercially available 3-(trifluoromethyl)phenol can be reduced to ahydroxy cyclohexane, oxidized with Dess-Martin reagent to the ketone,acylated with Mander's reagent, and followed by enamine formation. Usingsimilar methodologies illustrated above, compounds such as 90 may beobtained that possess a trifluoromethyl substituted cyclohexene.

Scheme 25 displays a strategy to access compounds of the structure 91.Commercially available 3-methyl-2-cyclohexen-1-one can be substituted togenerate a 3-geminal-dialkyl cyclohexanone. Upon acylation with Mander'sreagent, enamine formation, and following similar methodologiesillustrated above, compounds such as 91 may be obtained that possess ageminal dialkyl substituted cyclohexene.

Scheme 26 shows a method to access compounds of the structure 94.Commercially available pyridine 92 can be fluorinated and incorporatedinto a fluoro biaryl intermediate such as 93. Subsequent hydrolysis,acylation, and saponification following similar methodologiesillustrated above, may provide fluoropyridyl compounds such as 94.

Scheme 27 illustrates a method to generate compounds of the structure97. Commercially available 3-hydroxybenzaldehyde can be converted intothe ether substituted cyclohexane intermediate 95 via the key reductionof the phenyl ring. Upon ketone formation and similar methodologiesdescribed above, the ether substituted cyclohexene aminoester 96 can beobtained. This enamine intermediate may be acylated and deprotected asdescribed above, to generate compounds such as 97 that possess an ethersubstituted cyclohexene.

Scheme 28 displays methodology to access compounds of the structure 100.Commercially available tetrahydro-4-H-pyran-4-one can be converted intothe dihydropyran triflate intermediate 98 via similar methodologiesdescribed above. In parallel, commercially available6-methoxy-2-naphthaldehyde can be converted into the primary carboxamideintermediate 99, also via similar methodologies described above.Intermediates 98 and 99 may be coupled under similar metal catalyzedmethodology illustrated in Scheme 21, to generate compounds such as 100that possess a dihydropyran carboxylic acid moiety.

Scheme 29 illustrates a methodology to access compounds of the structure105. The ketone 101 (for preparation see Danishefsky, et al J. Am. Chem.Soc. 2004, 126, 14358) can be converted to the olefin 102, followed byreduction of the double bond using standard hydrogenation conditions,and acid catalyzed removal of the ketal protecting group to provide theketone 103. This material can be acylated using Mander's reagent to givethe desired ketoester that is converted to the enol trifate 104 withComins' reagent. Intermediates 104 and 99 may be coupled using similarmetal catalyzed methodology illustrated in Scheme 21. Saponification ofthe methyl ester using standard conditions can generate vicinaldisubstituted cyclohexene compounds such as 105.

The various organic group transformations and protecting groups utilizedherein can be performed by a number of procedures other than thosedescribed above. References for other synthetic procedures that can beutilized for the preparation of intermediates or compounds disclosedherein can be found in, for example, M. B. Smith, J. March AdvancedOrganic Chemistry, 5^(th) Edition, Wiley-Interscience (2001); R. C.Larock Comprehensive Organic Transformations, A Guide to FunctionalGroup Preparations, 2^(nd) Edition, VCH Publishers, Inc. (1999); T. L.Gilchrist Heterocyclic Chemistry, 3^(rd) Edition, Addison Wesley LongmanLtd. (1997); J. A. Joule, K. Mills, G. F. Smith Heterocyclic Chemistry,3^(rd) Edition, Stanley Thornes Ltd. (1998); G. R. Newkome, W. W.Paudler Contempory Heterocyclic Chemistry, John Wiley and Sons (1982);or Wuts, P. G. M.; Greene, T. W.; Protective Groups in OrganicSynthesis, 3^(rd) Edition, John Wiley and Sons, (1999), all sixincorporated herein by reference in their entirety.

REPRESENTATIVE EXAMPLES

The following examples are provided to more fully illustrate the presentinvention, and shall not be construed as limiting the scope in anymanner. Unless stated otherwise:

(i) all operations were carried out at room or ambient temperature (RT),that is, at a temperature in the range 18-25° C.;

(ii) evaporation of solvent was carried out using a rotary evaporatorunder reduced pressure (4.5-30 mmHg) with a bath temperature of up to50° C.;

(iii) the course of reactions was followed by thin layer chromatography(TLC) and/or tandem high performance liquid chromatography (HPLC)followed by mass spectroscopy (MS), herein termed LCMS, and any reactiontimes are given for illustration only;

(iv) yields, if given, are for illustration only;

(v) the structure of all final compounds was assured by at least one ofthe following techniques: MS or proton nuclear magnetic resonance (1HNMR) spectrometry, and the purity was assured by at least one of thefollowing techniques: TLC or HPLC;

(vi) ¹H NMR spectra were recorded on either a Varian Unity or a VarianInova instrument at 500 or 600 MHz using the indicated solvent; whenline-listed, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative toresidual solvent peaks (multiplicity and number of hydrogens);conventional abbreviations used for signal shape are: s. singlet; d.doublet (apparent); t. triplet (apparent); m. multiplet; br. broad;etc.;

(vii) MS data were recorded on a Waters Micromass unit, interfaced witha Hewlett-Packard (Agilent 1100) HPLC instrument, and operating onMassLynx/OpenLynx software; electrospray ionization was used withpositive (ES+) or negative ion (ES−) detection; the method for LCMS ES+was 1-2 mL/min, 10-95% B linear gradient over 5.5 min (B=0.05%TFA-acetonitrile, A=0.05% TFA-water), and the method for LCMS ES− was1-2 mL/min, 10-95% B linear gradient over 5.5 min (B=0.1% formicacid—acetonitrile, A=0.1% formic acid—water), Waters XTerra C18—3.5um—50×3.0 mmID and diode array detection;

(viii) automated purification of compounds by preparative reverse phaseHPLC was performed on a Gilson system using a YMC-Pack Pro C18 column(150×20 mm i.d.) eluting at 20 mL/min with 0-50% acetonitrile in water(0.1% TFA);

(ix) the manual purification of compounds by preparative reverse phaseHPLC (RPHPLC) was conducted on either a Waters Symmetry Prep C18—5um—30×100 mmID, or a Waters Atlantis Prep dC18—5 um—20×100 mmID; 20mL/min, 10-100% B linear gradient over 15 min (B=0.05% TFA-acetonitrile,A=0.05% TFA-water), and diode array detection;

(x) the purification of compounds by preparative thin layerchromatography (PTLC) was conducted on 20×20 cm glass prep plates coatedwith silica gel, commercially available from Analtech;

(xi) flash column chromatography was carried out on a glass silica gelcolumn using Kieselgel 60, 0.063-0.200 mm (SiO₂), or a Biotage SiO₂cartridge system including the Biotage Horizon and Biotage SP-1 systems;

(xii) chemical symbols have their usual meanings, and the followingabbreviations have also been used: h (hours), min (minutes), v (volume),w (weight), b.p. (boiling point), m.p. (melting point), L (litre(s)), mL(millilitres), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq or equiv (equivalent(s)), IC50 (molar concentrationwhich results in 50% of maximum possible inhibition), EC50 (molarconcentration which results in 50% of maximum possible efficacy), uM(micromolar), nM (nanomolar);

(xiii) definitions of acronyms are as follows:

BBr₃ is boron tribromide B(OMe)₃ is trimethyl borate Comins' reagent is2-[N,N- CDI is 1,1′- Bis(trifluromethylsulfonyl)amino]- carbonyldiimidazole 5-chloropyridine DCM is dichloromethane DIBALH is diisobutyl(methylene chloride) aluminum hydride DMF is dimethylformamide DMAP is4-dimethyl amino pyridine DMSO is dimethyl sulfoxide iPrMgCl isisopropyl magenisium chloride KHMDS is potassium bis LDA is lithium(trimethylsilyl) amide diisopropyl amide LiHMDS is lithium bis Mander'sreagent is (trimethylsilyl) amide methyl cyanoformate NBS isN-bromo-succinimide NaOCl is sodium hypochlorite NMO is 4-methylmorpholine N-oxide OTf is triflate Pd(PPh₃)₄ is tetrakistriphenylphosphine palladium (0) Pd₂(dba)₃ is Tris TBAF istetrabutylammonium (dibenzylideneacetone) fluoride; dipalladium (0); TBSChloride is t-bulyl TBSOTF is t-butyl dimethyl silyl dimethyl silylchloride trifluoromethane sulfonate TFA is trifluoroacetic acid THF istetrahydrofuran XANTPHOS is 9,9-Dimethyl-4,5-bis(diphenyl-phosphino)xanthene

Example 1

To a solution of methyl-2-oxocyclopentane-1-carboxylate (1.5 g, 10.55mmol) in methanol was added ammonium acetate (4.07 g, 52.76 mmol). Afterstirring the reaction at room temperature for 18 h, it was concentratedin vacuo. The residue was dissolved in DCM, washed with water, brine,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Thiscyclopentene aminoester intermediate was used without any furtherpurification.

To a solution of 3-(2-naphthyl)acrylic acid (1.5 g, 7.56 mmol) in 1:1ethanol-ethyl acetate (50 mL) was added Pd/C and the resulting mixturestirred under a H₂ balloon for 18 h. The reaction mixture was filteredthrough celite, and concentrated in vacuo to give the desired saturatednaphthyl acid as a white solid.

To a solution of this saturated naphthyl acid intermediate (150 mg, 0.75mmol) in DCM (6 mL) cooled to 0° C. was added DMAP (201 mg, 1.65 mmol)followed by methanesulfonyl chloride (0.059 mL, 0.75 mmol). After 5 min,the cyclopentene aminoester intermediate (95 mg, 0.67 mmol) was added asa solid. The mixture was stirred at RT for 18 h, and quenched withsaturated NH₄Cl solution. The resulting mixture was extracted with DCM.The organic layer was dried over anhydrous Na₂SO₄ filtered andconcentrated in vacuo. The residue was purified by flash chromatographyusing 10% ethyl acetate-hexanes as the eluant to give the desired amideproduct as a methyl ester.

To a solution of this ester intermediate (15 mg, 0.046 mmol) in THF (2mL), was added methanol (1 mL) followed by 1 N NaOH (1 mL). Theresulting reaction mixture was stirred at 23° C. for 6 h. It wasneutralized to pH=7 by the addition of 1N HCl and extracted with ethylacetate. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by reverse phase HPLC(Gilson) to provide Example 1. ¹H NMR (500 MHz, CD₃OD) δ 1.85 (m, 2H),2.49 (m, 2H), 2.8 (t, 2H), 3.1 (m, 4H), 7.4 (m, 3H), 7.7 (bs, 1H), 7.8(m, 3H); LCMS m/z 308 (M−1).

Preparation of Cyclohexene Aminoester and Enol Triflate EsterIntermediates

To a slurry of NaH (5.6 g, 60%) in 200 mL of THF was slowly added methylcyclohexanone 2-carboxylate (19.9 g, 90%) at 0° C. After 30 min, themixture was warmed to 23° C. and stirred for 15 min. The resultingmixture was cooled to 0° C., and to it was added Commin's reagent (50 g)in portions. The resulting mixture was warmed to RT and stirred for 2.5h. The solution was then concentrated, and the residue was partitionedbetween ethyl acetate and water. The organic layer was dried with sodiumsulfate and concentrated. The residue was purified by Biotage (5-10%ethyl acetate in hexane) to give the cyclohexene enol triflate ester.

To a solution of methyl cyclohexanone 2-carboxylate (10.3 g, 90%) in 100mL of methanol was added ammonium acetate (8.5 g). The resulting mixturewas stirred at room temperature overnight. The mixture was thenconcentrated, and the residue was dissolved in ethyl acetate. The solidwas filtered, and the filtrate was washed with water, brine and driedover sodium sulfate. The resulting solution was concentrated to give thecyclohexene aminoester as an oil, which crystallized from hexane as awhite solid.

Example 2

To a solution of the saturated naphthyl acid intermediate from Example 1(194 mg, 0.97 mmol) in DCM (6 mL), was added DMAP (236 mg, 1.93 mmol)followed by methanesulfonyl chloride (0.05 mL, 0.64 mmol). After 5 min,a solution of methyl 2-aminocyclohex-1-ene-1-carboxylate (100 mg, 0.64mmol) in DCM (1 mL) was added. The reaction mixture was stirred at RTfor 18 h, and quenched with saturated NH₄Cl solution. The resultingmixture was extracted with DCM dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyusing 7% ethyl acetate-hexanes to provide the amide as a methyl ester.

To a solution of this ester intermediate in THF (2 mL) was added MeOH (1mL) and 1N NaOH (1 mL). The resulting reaction mixture was stirred atroom temperature for 18 h, then neutralized to pH=7 by the addition of1N HCl, and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄, filtered, concentrated in vacuo and purified byreverse phase HPLC (Gilson) to provide Example 2. ¹H NMR (500 MHz,CD₃OD) δ 1.55 (m, 4H), 2.3 (m, 2H), 2.7 (t, 2H), 2.85 (m, 2H), 3.1 (t,2H), 7.45 (m, 3H), 7.66 (s, 1H), 7.77 (m, 3H); LCMS m/z 324 (M+1).

Example 3

To a solution of 6-methoxy-2-naphthaldehyde (3.6 g, 19.38 mmol) intoluene (100 mL) placed in a pressure vessel, was added(tert-butoxycarbonyl-methylene)triphenyl-phospharane (8.76 g, 23.25mmol). The resulting mixture was refluxed at 120° C. for 18 h. Thereaction mixture was concentrated in vacuo and purified using a Biotageflash 40M column with 15% ethyl acetate-hexanes as the eluant to givethe enoate intermediate.

To a solution of this tert-butyl-3-(6-methoxy-2-naphthyl)acrylate (4.88g, 17.16 mmol) in ethanol (100 mL) was added Pd/C. The resulting mixturewas stirred under a H₂ balloon for 18 h. The reaction mixture wasfiltered through celite and concentrated in vacuo to give the saturatedester as a white solid.

To a solution of this ether ester intermediate (150 mg, 0.52 mmol) inDCM cooled to 0° C., was added BBr₃ (5.23 mL, 1.0M in DCM). After 30min, the reaction mixture was quenched by the addition of methanol (2mL). The reaction mixture was concentrated in vacuo, and the residue wasdissolved in ethyl acetate and washed with water. The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography using 20% ethylacetate-hexanes as eluant. This transesterified methyl ester (97 mg,0.42 mmol) was dissolved in THF (3 mL) and MeOH was added (2 mL)followed by 1N NaOH (2 mL). After stirring for 6 h, the mixture wasneutralized to pH=7 by the addition of 1N HCl. The resulting solutionwas extracted with ethyl acetate, dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. This naphtholic acid was used in the nextstep without any further purification.

To a solution of this naphtholic acid (106 mg, 0.49 mmol) in DCM (5 mL)cooled to 0° C., was added TBSOTf (0.17 mL, 0.73 mmol) followed bytriethylamine (0.14 mL, 0.98 mmol). After warming the mixture to 23° C.and stirring for 2 h, it was quenched by the addition of water. Theresulting mixture was extracted with DCM, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. This bis-silylated material wasdissolved in 1:1 THF/H₂O (2 mL) and AcOH (3 mL) was added. Afterstirring the mixture at RT for 1 h, it was diluted with water andextracted with ethyl acetate. The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the desired acidintermediate.

To a solution of this acid (51 mg, 0.154 mmol) in DCM (2 mL), was addedDMAP (48 mg, 0.39 mmol) followed by methanesulfonyl chloride (0.012 mL,0.154 mmol). After 5 min, methyl 2-aminocyclohex-1-ene-1-carboxylate (20mg, 0.128 mmol) was added as a solid. The reaction mixture was heated to50° C. for 18 h, and then cooled to RT and quenched by the addition ofsaturated ammonium chloride. The resulting mixture was extracted withDCM, dried over anhydrous Na₂SO₄ filtered and concentrated in vacuo. Theresidue was purified by flash chromatography using 10% ethylacetate-hexanes as the eluant to provide the amide product.

To a solution of this intermediate ester (109 mg, 0.23 mmol) in THF (3mL), was added 1N NaOH (1 mL) followed by MeOH (1.5 mL). After thereaction was complete, it was neutralized to pH=7 by the addition of 1NHCl. The resulting mixture was extracted with ethyl acetate, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by reverse phase HPLC (Gilson) to provide Example 3. ¹H NMR(500 MHz, DMSO-d₆) δ 1.5 (m, 4H), 2.2 (bt, 2H), 2.63 (t, 2H), 2.8 (bt,2H), 2.92 (t, 2H), 7.1 (m, 2H), 7.27 (d, 1H), 7.52 (m, 2H), 7.65 (d,1H), 9.6 (bs, 1H), 11.6 (bs, 1H), 12.5 (bs, 1H); LCMS m/z 338 (M−1).

Example 4

To a solution of methyl 3-(3-bromophenyl)propionate (100 mg, 0.411 mmol)in toluene (2 mL) was added phenyl boronic acid (100 mg, 0.82 mmol), 1MNa₂CO₃ solution (1 mL) followed by Pd(PPh₃)₄. The resulting reactionmixture was refluxed in a pressure tube. After 2 h the mixture wascooled to 23° C., diluted with ethyl acetate, washed with water, brine,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography using 10% ethylacetate-hexanes to give the biaryl product.

To a solution of this ester intermediate (85 mg, 0.35 mmol) in THF (1mL) was added MeOH (1 mL) and 5N NaOH (1 mL). After stirring for 1 h,the reaction mixture was neutralized to pH=7 by the addition of 1N HCl.The resulting mixture was extracted with ethyl acetate, and the organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The acid was used in the next step without any furtherpurification. This acid intermediate was coupled tomethyl-2-amino-cyclohexene using the similar procedures as described inthe Examples above. Example 4 was prepared by saponification of thepenultimate ester using similar procedures as described in the Examplesabove. ¹H NMR (500 MHz, CD₃OD) δ 1.6 (m, 4H), 2.3 (m, 2H), 2.68 (t, 2H),2.85 (m, 2H), 3.01 (t, 2H), 7.2 (d, 1H), 7.35 (m, 2H), 7.45 (m, 4H),7.58 (d, 2H); LCMS m/z 348 (M−1).

Example 5

The coupling of 3-(3-bromophenyl) propionic acid with methyl2-aminocyclohex-1-ene-1-carboxylate followed the similar procedures asdescribed in the Examples above. To a solution of this aryl bromideintermediate (50 mg, 0.136 mmol) and 4-hydroxy-phenyl boronic acid (28mg, 0.2 mmol) in THF (0.5 mL), was added K₂CO₃ (0.5 mL, 1.0M solution),followed by 1,1(bis-tert-butyl-phosphino) ferrocene palladium dichlorideligand. The reaction vessel was flushed with N₂ and heated to 85° C.After 30 min, the reaction mixture was cooled to RT and diluted withethyl acetate. The resulting mixture was washed with water, brine, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography using 15% ethyl acetate-hexanes asthe eluant to obtain the hydroxy biaryl methyl ester.

This intermediate ester was saponified following similar proceduresdescribed in the Examples above. ¹H NMR (500 MHz, DMSO-d₆) δ 1.55 (m,4H), 2.24 (m, 2H), 2.63 (t, 2H), 2.80 (bt, 2H), 2.9 (t, 2H), 6.83 (d,2H), 7.13 (d, 1H), 7.33 (t, 1H), 7.38 (d, 1H), 7.42 (s, 1H), 7.45 (d,2H), 9.52 (s, 1H); LCMS m/z 364 (M−1).

Example 6

To a solution of diisopropylamine (5.3 g, 52 mmol) in 200 mL of THF wasadded n-butyllithium (22.4 mL, 56 mmol, 2.5 M in hexane) at −78° C. Theresulting solution was stirred at −78° C. for 30 min, and then at RT foran additional 30 min. The solution was re-cooled to −78° C., and to thissolution, was added dropwise a solution of tetralone 20 (7.03 g, 39.9mmol) in 80 mL of THF. After 1 h at −78° C., to the above solution wasadded 4-chloro-4-oxobutyrate (8.43 g, 6.84 mL, 56 mmol) in one portion.The resulting solution was warmed to 23° C. over 2 h. The solvent wasthen evaporated, and the residue was diluted with 200 mL ofTHF/MeOH/water (v:v:v=3:1:1). To this mixture was added 100 mL oflithium hydroxide (1 M in water), and the resulting solution was stirredovernight. After removing some solvent in vacuo, the remaining aqueouslayer was extracted with ethyl acetate. The aqueous phase was acidifiedwith HCl until pH=3. The mixture was extracted with ethyl acetate, andthe combined organic fractions were dried with sodium sulfate andconcentrated in vacuo to give the ketoacid as a grey solid.

To a solution of this ketoacid intermediate (0.72 g, 2.6 mmol) in 15 mLof ethanol were added hydroxylamine hydrochloride (0.22 g, 3.1 mmoL) andtriethylamine (320 mg, 0.44 mL, 3.1 mmol). The resulting mixture washeated at reflux for 5 h. After removing ethanol in vacuo, the residuewas diluted with ethyl acetate (100 mL) and 1N HCl (20 mL). The aqueouslayer was further extracted with 30% of isopropanol in chloroform (2×30mL). The organic fractions were combined, dried with sodium sulfate andconcentrated in vacuo to give the tricycle as a pale yellow solid. Thisintermediate was dissolved in dichloromethane (20 mL) andborontribromide (10 mL, 1 M in dichloromethane) was added at 0° C. Theresulting dark solution was stirred at room temperature for 4 h beforeit was quenched with 100 mL of water at 0° C. The mixture was extractedwith 30% isopropanol in chloroform. The aqueous layer contained a lot ofproduct as a yellow solid, which was collected by filtration. Theaqueous layer was further extracted with 30% isopropanol in chloroform.The organic phase was dried with sodium sulfate and concentrated invacuo to give the hydroxy product as a yellow solid after reversephase-HPLC purification.

To a solution of this hydroxy acid intermediate (110 mg, 0.42 mmol) in15 mL of dichloromethane were added imidazole (87 mg, 1.3 mmol) andtert-butyldimethylsilyl chloride (192 mg, 1.3 mmoL) at RT. The resultingmixture was stirred for 4 h. The mixture was then purified by Biotage togive the product as a colorless oil.

To a solution of this bis-silyl intermediate (50 mg, 0.10 mmol) in 3 mLof dichloromethane were added 1 drop of DMF and oxalyl chloride (0.13mL, 0.25 mmol, 2 M in dichloromethane) at 0° C. After 2 h at 0° C., themixture was warmed to room temperature and stirred for 30 min. Thevolatiles were removed in vacuo, and to the residue was added 2 mL ofdichloromethane followed by methyl 2-aminocyclopent-1-ene-1-carboxylate(35 mg, 0.25 mmol). The mixture was stirred overnight and then DMAP (10mg) was added. The resulting mixture was stirred for an additional 2 h.The crude mixture was directly purified by Biotage (2-10% ethylacetate/hexane) to give the amide product as a colorless oil.

To a solution of this silyl ether methyl ester intermediate (14 mg,0.023 mmol, 23%) in 5 mL of THF/MeOH/water (v:v:v=3:1:1), was added 1 Nsodium hydroxide (1 mL) and 3 drops of TBAF (1 M in THF). After 5 min at23° C., the mixture was concentrated in vacuo and the residue wasdissolved in DMSO, which was purified by reverse phase HPLC (Gilson) togive a colorless oil. This material was then dissolved in 3 mL ofTHF/MeOH/water (v:v:v=3:1:1). To this solution was added lithiumhydroxide (2 mL, 1 M in water). The resulting mixture was stirred atroom temperature for 3 h. The mixture was concentrated and dissolved inDMSO. The mixture was purified by reverse phase HPLC (Gilson) to provideExample 6 as a light brown solid. ¹H NMR (acetone-d₆, 500 MHz) δ 10.4(1H, s), 7.44 (1H, d), 6.85 (s, 1H), 6.80 (1H, dd), 3.13 (2H, t), 2.98(4H, q), 2.83 (2H, t), 2.73 (2H, t), 2.49 (2H, t), 1.87 (2H, t); LCMSm/z 369 (M+1).

Examples 7-15

The following compounds were prepared under conditions similar to thosedescribed in Examples 1-6 above and illustrated in Schemes 1-6. Example15 utilized triethylamine as base instead of imidazole/DMAP describedfor the TBSCl silylation step in Example 6.

EXAMPLE LCMS 7

322 (M − 1) 8

336 (M − 1) 9

348 (M − 1) 10

364 (M − 1) 11

364 (M − 1) 12

363 (M − 1) 13

390 (M − 1) 14

334 (M − 1) 15

383 (M + 1)NMR data for selected Examples:

Example 7

¹H NMR (500 MHz, DMSO-d₆) δ 1.5 (m, 4H), 2.2 (bt, 2H), 2.65 (t, 2H), 2.8(bt, 2H), 3.34 (t, 2H), 7.4 (m, 2H), 7.54 (m, 2H), 7.78 (d, 1H), 7.92(d, 1H), 8.08 (d, 1H).

Example 8

¹H NMR (500 MHz, CD₃OD) δ 0.9 (d, 3H), 1.3 (m, 1H), 1.57 (m, 1H), 1.7(m, 1H), 2.24 (m, 1H), 2.35 (m, 1H), 2.45 (m, 1H), 2.7 (t, 2H), 3.05(dd, 1H), 3.1 (t, 2H), 7.34-7.43 (m, 3H), 7.65 (s, 1H), 7.72 (m, 3H).

Example 9

¹H NMR (500 MHz, DMSO-d₆) δ 1.55 (m, 4H), 2.2 (bt, 2H), 2.6 (t, 2H), 2.8(bt, 2H), 2.9 (t, 2H), 7.3 (m, 3H), 7.44 (t, 2H), 7.56 (d, 2H), 7.62 (d,2H), 11.6 (bs, 1H).

Example 10

¹H NMR (500 MHz, DMSO-d₆) δ 1.55 (m, 4H), 2.4 (t, 2H), 2.62 (t, 2H),2.84 (bt, 2H), 2.9 (t, 2H), 6.85 (t, 1H), 6.95 (d, 1H), 7.15 (m, 2H),7.22 (d, 1H), 7.3 (t, 1H), 7.38 (m, 2H), 9.4 (s, 1H), 11.6 (s, 1H),12.55 (bs, 1H).

Example 11

¹H NMR (500 MHz, DMSO-d₆) δ 1.55 (m, 4H), 2.24 (bt, 2H), 2.66 (t, 2H),2.82 (bt, 2H), 2.94 (t, 2H), 6.75 (d, 1H), 6.9 (m, 1H), 7.05 (d, 1H),7.25 (m, 2H), 7.35 (t, 1H), 7.4 (d, 1H), 7.45 (s, 1H), 9.49 (s, 1H).

Example 12

¹H NMR (500 MHz, DMSO-d₆) δ 1.55 (m, 4H), 2.22 (bt, 2H), 2.62 (t, 2H),2.8 (bt, 2H), 2.9 (t, 2H), 6.9 (d, 1H), 7.2 (m, 3H), 7.3-7.4 (m, 3H),7.44 (s, 1H), 11.6 (s, 1H).

Example 13

¹H NMR (500 MHz, DMSO-d₆) δ 1.55 (m, 4H), 2.2 (m, 2H), 2.6 (t, 2H), 2.8(m, 2H), 2.9 (t, 2H), 3.2 (t, 2H), 4.55 (t, 2H), 6.82 (d, 1H), 7.14 (d,1H), 7.3 (t, 1H), 7.39 (m, 2H), 7.42 (s, 1H), 7.49 (s, 1H), 11.62 (s,1H), 12.5 (bs, 1H).

Example 14

¹H NMR (500 MHz, DMSO-d₆) δ 1.75 (m, 2H), 2.35 (bt, 2H), 2.7 (t, 2H),2.85 (t, 2H), 3.02 (t, 2H), 7.35 (m, 3H), 7.44 (t, 2H), 7.56 (d, 2H),7.62 (d, 2H).

Example 15

¹H NMR (acetone-d₆, 500 MHz) δ 11.8 (1H, s), 7.43 (1H, d), 6.81 (1H, d),6.80 (1H, dd), 2.96 (8H, m), 2.72 (4H, q), 1.61 (4H, m).

Example 16

A solution of the aldehyde intermediate (1.45 g, 6.7 mmol), ethyltriphenylphosphonium methyl acetate (3.1 g, 8.1 mmol) in 15 mL oftoluene was heated at 130° C. for 16 h. The mixture was directlypurified by Biotage (5-20% ethyl acetate in hexane) to give the enoateas a light yellow solid.

This enoate intermediate (1.74 g, 5.8 mmol) and Pd/C (10%, 170 mg) in200 mL of methanol was stirred under 1 atm of hydrogen gas (balloon) for12 h. The slurry was filtered and concentrated in vacuo. The residue wasdissolved in ethanol/methanol (1:1) and purified by chiral OJ-H (9mL/min, 28% isopropanol/heptane, isocratic, 40 min/run) to give theenantiomers as white solids. Elution times of these enantiomericintermediates were 18 min and 22 min using analytical Chiralcel-OJ, (25%isopropanol in heptane, isocratic).

The ethyl ester enantiomer (400 mg, 1.32 mmoL) was combined withconcentrated HCl (2 mL) and 4 mL of acetic acid, and was heated at 80°C. for 3 h. The mixture was concentrated in vacuo, and to it was added15 mL of water. The mixture was extracted with 30%isopropanol/chloroform. The organic layer was dried with sodium sulfateand concentrated in vacuo to give the acid product as a white solid.

To a solution of the methyl ether (410 mg, 1.50 mmol) in 20 mL ofdichloromethane was added borontribromide (7.5 mL, 1 M indichloromethane) at 0° C. The mixture was warmed to RT and stirred for18 h. The mixture was quenched with water at 0° C. and concentrated invacuo without further purification.

To a solution of the phenol in 60 mL of dichloromethane were added TBSCl(0.57 g, 3.8 mmol), imidazole (0.26 g, 3.8 mmol) and DMAP (37 mg, 0.3mmol). The mixture was stirred at 23° C. for 5 h. The mixture wasconcentrated and purified by RP-HPLC to give monosilyl ether (0.37 g),which was resubmitted to a solution of TBSCl (225 mg), triethylamine(0.21 mL) and DMAP (20 mg) in 15 mL of dichloromethane. The reactionmixture was stirred for 3 h and washed with brine. The mixture was thendried with sodium sulfate and concentrated in vacuo to give thebis-silylated intermediate as a crude brown oil. Following thepreviously described amide formation and hydrolysis procedures usingoxalyl chloride and lithium hydroxide respectively, the enantiomers ofExample 16 were obtained. ¹H NMR (methanol-d₄, 500 MHz) δ 7.41 (1H, s),7.16 (2H, d), 6.88 (2H, d), 3.07 (2H, m), 2.73 (3H, m), 2.46 (2H, m),2.15 (3H, s), 1.87 (2H, m), 1.23 (3H, d); LCMS m/z 370 (M+1).

Example 17

The enantiomers of Example 17 were prepared under similar conditions asdescribed in the Examples above. ¹H NMR (methanol-d₄, 500 MHz) δ 7.43(1H, s), 7.18 (2H, dd), 6.89 (2H, dd), 2.86 (2H, m), 2.76 (1H, dd), 2.63(1H, dd), 2.58 (1H, m), 2.30 (2H, m), 2.16 (3H, s), 1.60 (4H, m), 1.23(3H, d); LCMS m/z 384 (M+1).

Example 18

A mixture of the methoxy aminobenzothiazole (8.5 g, 47 mmoL) and ethylα-bromopyruvate (12.9 g, 59 mmol) was heated in 120 mL of DME underreflux for 2 h. After cooling to RT, the precipitate was collected byfiltration to afford the product as a yellow solid, which was thenheated in a solution of ethanol (200 mL) under reflux for 4 h. Thepartitioning of the resulting residue after concentration using ethylacetate and saturated aqueous sodium carbonate solution gave an organicfraction, which was dried with sodium sulfate. The concentration invacuo led to the tricyclic intermediate as a solid.

To a solution of this ester (2.67 g, 9.65 mmol) in 100 mL ofdichloromethane was added DIBALH (14.5 mL, 1 M in hexane, 14.5 mmol) at−78° C. After 1 h at −78° C., the mixture was quenched with water andslowly warmed to 23° C. A saturated aqueous Rochelle's salt solution wasadded, and the mixture turned clear overnight. The organic phase waswashed with water and concentrated. The resulting residue was filteredto give the aldehyde as a yellow solid.

To a solution of trimethyl phosphonoacetate (0.71 mL, 4.33 mmol) in 40mL of THF was added nBuLi (2.9 mL, 4.6 mmoL, 1.6 M in hexane) at 0° C.After 30 min, to the solution was added the aldehyde (0.67 g, 2.88mmol). After 10 min, the mixture was quenched with water and dilutedwith ethyl acetate. The organic phase was concentrated and purified byBiotage (20-30% ethyl acetate/hexane) to give the enoate as a whitesolid.

To a solution of this enoate intermediate (0.43 g, 1.49 mmol) in 200 mLof methanol was added tosylhydrazide (2.77 g, 14.9 mmol). The mixturewas heated under reflux for overnight. The resulting clear solution wasconcentrated and purified by Gilson to give the product as a whitesolid.

To a solution of this ester (230 mg) in 50 mL of THF/MeOH/water(v:v:v=3:1:1) was added 10 mL of 1 N aqueous LiOH solution. After 1.5 h,the mixture was acidified using HCl to pH=4. The mixture was extractedwith 30% of isopropanol in chloroform. The organic phase wasconcentrated to dryness to give the acid as a white solid.

To a solution of the methyl ether (220 mg, 0.80 mmol) in 40 mL ofdichloromethane was added borontribromide (6.4 mL, 1 M indichloromethane) at 0° C. The mixture was warmed to RT and stirred for12 h. The mixture was quenched with water at 0° C. and washed with 30%of isopropanol in chloroform. After concentration of the organicsolvent, the product was obtained as a solid.

To a solution of this phenol in 60 mL of dichloromethane were addedTBSCl (380 mg) and triethylamine (3 mL). The reaction mixture wasstirred for 3 h and washed with water. After concentration of theorganic fraction, the residue was purified by RP-HPLC to give themono-TBS product (0.26 g), which was resubmitted to a solution of TBSCl(156 mg), triethylamine (0.24 mL) and DMAP (13 mg) in 60 mL ofdichloromethane. The reaction mixture was stirred at 0° C. for 1 hr, andto the mixture was added additional 1 equivalent of triethylamine andTBSCl. The solution was stirred overnight at RT before it washed withwater. The organic phase was then dried with sodium sulfate andconcentrated in vacuo to give the bis-silylated product as a crude brownoil. Following the previously described amide formation and hydrolysisprocedures using oxalyl chloride and lithium hydroxide respectively,Example 18 was obtained. ¹H NMR (methanol-d₄, 500 MHz) δ 8.13 (1H, s),7.88 (1H, d), 7.41 (1H, d), 7.11 (1H, dd), 3.16 (4H, m), 2.89 (2H, t),2.50 (2H, t), 1.91 (2H, m); LCMS m/z 372 (M+1).

Example 19

Example 19 was prepared under similar conditions as described in theExamples above. ¹H NMR (methanol-d₄, 500 MHz) δ 8.04 (1H, s), 7.83 (1H,d), 7.37 (1H, d), 7.08 (1H, dd), 3.12 (2H, t), 2.93 (2H, m), 2.81 (2H,t), 2.34 (2H, m), 1.65 (4H, m); LCMS m/z 386 (M+1).

Example 20

To a solution of adiponitrile (0.569 mL, 5.0 mmol) in anhydrous THFcooled to −78° C. under a nitrogen atmosphere, was added LDA (2.62 mL,5.25 mmol, 2.0 M solution in THF). The reaction was warmed to −20° C.over 10 min, and then quenched with saturated NH₄Cl solution. Theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. This material was purified by flashchromatography using 15% ethyl acetate-hexanes as the eluant to give thecyclopentene aminonitrile as an off white solid. This intermediatecyclopentene aminonitrile was coupled with 3-(4-bromophenyl) propionicacid, using similar procedures as described in the Examples above, toprovide the amide bromide.

To a solution of this arylbromide intermediate (88 mg, 0.28 mmol) in THF(0.5 mL) was added phenyl boronic acid (48 mg, 0.41 mmol) followed by 1MK₂CO₃ (0.5 mL) and 1,1bis(di-tert-butylphosphino)ferrocene palladiumdichloride ligand (18 mg, 0.03 mmol). After stirring the reaction in asealed tube at 85° C. for 18 h, it was diluted with ethyl acetate,washed with H₂O and saturated NaCl. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspuffed by flash chromatography using 10% ethyl acetate-hexanes to givethe biaryl intermediate as a colorless oil.

To a solution of this intermediate nitrile (34 mg, 0.11 mmol) in a 2:1mixture of dioxane-H₂O (0.9 mL) was added sodium azide (21 mg, 0.32mmol) and zinc bromide (29 mg, 0.13 mmol). The reaction mixture wasstirred at 120° C. in a sealed tube for 18 h. The mixture was thencooled to room temperature and 1N HCl was added until the pH=7. Thereaction mixture was concentrated in vacuo and purified by reverse phaseHPLC (Gilson) to provide Example 20. ¹H NMR (500 MHz, CD₃OD) δ 2.02 (m,2H), 2.46 (m, 2H), 2.85 (m, 2H), 3.15 (m, 4H), 7.18 (d, 2H), 7.31 (t,1H), 7.41 (t, 2H), 7.52 (d, 2H), 7.56 (t, 2H); LCMS m/z 360 (M+1).

Example 21

To the commercially available thiazole bromo aldehyde (4.97 g) shown inScheme 10, in 200 mL of methanol was added NaBH₄ (0.98 g) in portions at0° C. The mixture was stirred for 2 h and concentrated. The residue wassuspended in saturated NH₄Cl solution (200 mL) to adjust the pH to 6.The mixture was then basified by NaOH (aq) to pH 11 before theextraction with ethyl acetate (4×200 mL). The combined organic fractionswere dried with sodium sulfate and concentrated to give the alcohol.

To a solution of this hydroxy intermediate (4.91 g) in 120 mL ofdichloromethane at 0° C. was added triphenylphosphine (9.96 g). To thissolution was then added dropwise, carbon tetrabromide (12.6 g) in 30 mLof dichloromethane. After 2.5 h at 23° C., the mixture was stirred at−20° C. overnight. The solvent was then removed, and the residue waspurified by Biotage (5-10% ethyl acetate in hexane) to give the bromideas a white solid.

To a solution of diethyl methylmalonate (5.19 g) in 100 mL of THF wasadded NaH (1.2 g, 60%) at 0° C. in portions. The mixture was stirred at0° C. for 10 min, and to this solution was then added the bromideintermediate (3.84 g) in one portion. The mixture was warmed to 23° C.and stirred for 1 h before the addition of water. The resulting mixturewas extracted with ethyl acetate, concentrated and purified by Biotage(5-10% ethyl acetate in hexane) to give the diester containing somediethyl methyl malonate contaminant as a crude oil.

To this diester (5 g) was added THF/MeOH/water (˜100 mL, 3:1:1), LiOH(˜50 mL, 1 N) at 23° C. The resulting solution was stirred overnight.After the removal of the organic solvent, to the residue was addedconcentrated HCl until pH=4. The mixture was extracted with ethylacetate (5×100 mL). The combined organic layers were dried with sodiumsulfate and concentrated to give the diacid as a white solid containingsome α-methyl malonate acid contaminant.

The solution of this diacid intermediate (4.9 g) in 20 mL of DMF washeated at 150° C. for 7 min and then cooled to 0° C. The solution wasdiluted with ethyl acetate, washed with brine, dried with sodium sulfateand concentrated to give the monoacid containing some propanoic acid.The mixture was further purified by RP-HPLC to give purealpha-methylacid as a colorless oil.

The mixture of this bromoacid intermediate (0.71 g), the aryl boronicacid (0.67 g), Pd(PPh₃)₄ (323 mg), NaHCO₃ solution (11.2 mL, 1 N) anddioxane (40 mL) was heated at 100° C. under nitrogen overnight in asealed tube. The mixture was then partitioned between ethyl acetate and1 N NaOH solution. The organic layer was washed with 1 N NaOH solution.The combined aqueous layers were acidified with concentrated HCl untilpH=4-5. The resulting mixture was extracted with ethyl acetate threetimes. The combined organic layers were washed with brine and dried withsodium sulfate. The removal of solvent afforded the biaryl product.

To a solution of the methoxyaryl intermediate (0.88 g) in 60 mL ofdichloromethane was added BBr₃ (22.7 mL, 1 M in dichloromethane) at 0°C. The mixture was warmed to room temperature and stirred overnight. Tothe mixture was then added water at 0° C., and the mixture was extractedwith 30% isopropanol in chloroform. After concentrating the organiclayer, the residue was hydrolyzed with LiOH (1 N) in 3:1:1THF/MeOH/water for 2 h. After the removal of the organic solvent, theresidue was washed with ethyl acetate. The alkaline aqueous phase wasacidified with HCl until pH=4-5, and the mixture extracted with ethylacetate (2×). The combined organic layers were washed with brine, driedwith sodium sulfate and concentrated to give the phenol as a brownsolid.

To a mixture of this phenolic acid intermediate (0.51 g) in 10 mL ofdichloromethane was added triethylamine (0.84 mL). To this solution at0° C. was added tert-butyldimethylsilyl chloride (0.91 g) and DMAP (42mg). After 6 h at 23° C., the mixture was washed with water, brine anddried with sodium sulfate. The resulting organic fraction wasconcentrated in vacuo. To the resulting residue in dichloromethane (40mL) was added one drop of DMF, and then a solution of oxalyl chloride (4mL, 2 N in dichloromethane). The mixture was warmed to 23° C. andstirred for additional 4 h. The resulting mixture was concentrated invacuo and then dissolved in dichloromethane (28 mL). To the resultingsolution was then added the enamine fragment (717 mg) as in the examplesabove. The resulting mixture was stirred for overnight. The crudematerial was purified by RP-HPLC to give 430 mg of amide. To theresulting amide was added 6 mL of THF:methanol:water (3:1:1) and asolution of lithium hydroxide (10 mL, 1N). After 5 h, most of the lowboiling solvent was removed in vacuo. To the residue was addedconcentrated HCl until pH=3. The mixture was extracted with 30%isopropanol in chloroform. The organic layer was concentrated andpurified by RP-HPLC to give the desired Example 21. ¹H NMR (DMSO-d₆, 500MHz) δ 12.6 (1H, s), 11.6 (1H, s), 10.4 (1H, s), 7.95 (1H, d), 7.62 (1H,s), 6.94 (1H, d), 6.85 (1H, dd), 3.10 (1H, dd), 2.89 (1H, dd), 2.79 (2H,m), 2.62 (1H, m), 2.20 (2H, m), 1.52 (4H, m), 1.15 (3H, d); LCMS m/z 421(M+1).

Example 22

To the intermediate alpha-methylacid bromothiazole above (197 mg,Compound 52 in Scheme 11) in dichloromethane (10 mL) was added one dropof DMF, and then a solution of oxalyl chloride (1.6 mL, 2 N indichloromethane). The mixture was warmed to room temperature and stirredfor 1 h. The resulting mixture was concentrated in vacuo and thendissolved in dichloromethane (10 mL). To the resulting solution was thenadded the common 2-aminocyclohex-1-ene-1-carboxylate ester (400 mg). Theresulting mixture was stirred overnight. The crude material was purifiedby Biotage (5-10% ethyl acetate in hexane) to give the amide as acolorless oil.

The mixture of this bromo intermediate (55 mg), phosphine ligand (14mg), K₂CO₃ (440 mg, in 3.2 mL of water) in THF (4 mL) was degassed withargon followed by the addition of boronate ester (35 mg). The mixturewas heated at 55° C. for 1 h and then 65° C. overnight. The resultingmixture was partitioned between ethyl acetate and brine. The organiclayer was dried with sodium sulfate and purified by RP-HPLC to give thebiaryl product. The similar hydrolysis procedure as described in theExamples above gave Example 22 as a white solid. ¹H NMR (DMSO-d₆, 500MHz) δ 11.6 (1H, s), 8.05 (1H, s), 7.43 (1H, d), 3.04 (1H, dd), 2.90(1H, dd), 2.76 (2H, m), 2.58 (1H, m), 2.18 (2H, m), 1.50 (4H, m), 1.13(3H, d); LCMS m/z 361 (M+1).

Example 23

To NaH (7.2 g, 60%) was added DMF (100 mL) followed by 4-methoxybenzylalcohol (18.7 mL) at 0° C. After 25 min at 0° C., the mixture was warmedto 23° C. and stirred for additional 30 min. To the resulting solutionwas added the pyridyl cyanobromide (22.9 g) in one portion. The reactionwas exothermic and stirred for 10 min before it was cooled to roomtemperature. The mixture was diluted with 500 mL of ethyl acetate,washed with water (500 mL×3). The first two aqueous phases wereextracted with dichloromethane (500 mL×2). The combined dichloromethanephase was washed with water (500 mL×3). The combined organic phases weredried over sodium sulfate and concentrated to give the PMB ether as awhite solid.

To the suspension of this intermediate (24.6 g) and hydroxylaminehydrochloride (8.55 g) in ethanol (500 mL) was added NaOH (4.92 g in 50mL of water) dropwise. The mixture was stirred at RT overnight. Thesolid was collected by filtration to give the N-hydroxy amidine as awhite solid.

To this amidine intermediate (15.4 g) was added pyridine (40 mL) and theacid chloride shown in Scheme 12 (8.3 mL). The mixture was heated at120° C. for 2 h and then 130° C. for 1 h. After removing most pyridine,the residue was partitioned between water and dichloromethane. Theorganic phase was washed with water four times and then dried withsodium sulfate. After removing the solvent, to the residue was addedsome methanol. The resulting slurry was filtered. The solid collected bythe filtration was washed with methanol and dried in vacuo to give themethyl ester intermediate as a pale pink solid.

To this ester (30 g) suspended in 3:1:1 THF/MeOH/water (700 mL) wasadded LiOH (300 mL, 1 N). The mixture was stirred at RT for 1 h. Afterremoving most of the solvent, the aqueous layer was acidified to pH=3.Filtration of the resulting slurry gave a white solid, which was washedwith water, diethyl ether and azeotroped with toluene to give the acidas a white solid.

To a mixture of this acid (26.9 g) in 300 mL of dichloromethane wereadded 0.1 mL of DMF, and then a solution of oxalyl chloride (76 mL, 2 Nin dichloromethane) at 0° C. After 0.5 h, the mixture was warmed to RTand stirred for additional 0.5 h. The resulting mixture was concentratedin vacuo and then dissolved in dichloromethane (250 mL). To theresulting solution was then added the methyl2-aminocyclohex-1-ene-1-carboxylate (29 g). The resulting mixture wasstirred for overnight. The solution was then washed with water (200 mL),saturated sodium bicarbonate solution (200 mL) and dried with sodiumsulfate to give the amide as a crude material.

To a solution of the PMB ether intermediate (10.2 g) in 50 mL ofdichloromethane was added triisopropylsilane (12.3 mL) andtrifluoroacetic acid (20 mL) dropwise. The mixture was stirred at RT for10 min, and the solvent was removed in vacuo. To the residue containingthis hydroxy product was added 300 mL of THF:methanol:water (3:1:1)followed by a solution of lithium hydroxide (200 mL, 1N). After 12 h,most of the low-boiling solvent was removed in vacuo. To the residue wasadded ethyl acetate (200 mL×2), then the aqueous layer was neutralizedto pH=5. The precipitate was collected by filtration to give the desiredExample 23 as a light brown solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.6 (1H,s), 11.7 (1H, s), 10.6 (1H, s), 8.25 (1H, d), 7.88 (1H, d), 7.29 (1H,dd), 3.18 (2H, t), 2.89 (2H, t), 2.48 (2H, m), 2.21 (2H, m), 1.51 (4H,m); LCMS m/z 359 (M+1).

Example 24

To a flask containing 20 mL diglyme and KH (1.33 g, 30%) at roomtemperature was added methylpyrazole (820 mg) in one portion. After 2 h,to this mixture was added the pyridyl nitrobromide (1.83 g). The mixturewas then heated at 130° C. overnight. To the resulting mixture was added100 mL of water and 100 mL of ethyl acetate. The aqueous layer wasextracted with 100 mL of dichloromethane. The combined organic layerswere dried with sodium sulfate and concentrated in vacuo to give a greenslurry. To the slurry was added hexane to remove the mineral oil. Themixture was then filtered to give the pyridylpyrazole as a green solid.

The mixture of this methylated intermediate (204 mg), NBS (330 mg) and 5mL of CCl₄ under light was refluxed for 3.5 h. The mixture was filteredand the filtrate was washed with saturated aqueous sodium sulfite (100mL). The mixture was extracted with 30% of isopropanol in chloroform.The organic layer was washed with water, dried with sodium sulfate andconcentrated. The residue was purified by Biotage eluting with 5-30%ethyl acetate in hexane/dichloromethane to give the bromide as a lightyellow solid.

To NaH (350 mg, 60%) in 20 mL of THF was added dimethyl malonate (1.14g) at 0° C. After 20 min, to the clear solution was added thebromomethylene intermediate (490 mg) in 10 mL of THF dropwise. Themixture was warmed to RT and stirred for additional 1 h. To the mixturewas then added water (50 mL). The mixture was extracted with ethylacetate (200 mL). The combined organic layers were concentrated, and theresidue was submitted to 10 mL of LiOH (1N) and 50 mL of THF/MeOH/water(3:1:1). After 3 h, the mixture was acidified to pH=4 using concentratedHCl. The mixture was concentrated to remove organic solvents, and theresidue was extracted with 30% isopropanol in chloroform. The organiclayer was concentrated and purified by RP-HPLC to give the acidester.The mixture of this alpha-carboxyacid (1 g) in 10 mL of DMF was heatedat 150° C. for 10 min. The mixture was then purified by RP-HPLC to givethe monoester (880 mg) as a yellow solid. To this nitro intermediate(100 mg) in 6 mL of acetic acid was added Zn (234 mg). The slurry washeated at 60° C. for 30 min and filtered through celite. The filtratedwas purified by RP-HPLC to give the amino methyl ester as a reddish oil.

To the mixture of this aminopyridine (580 mg), sodium nitrite (200 mg)was added in 2.5 mL of 10% sulfuric acid. The mixture was heated at 80°C. for 1 h. The mixture was purified by RP-HPLC to give thehydroxypyridine. To this hydroxyacid (86 mg) was added 5 mL ofdichloromethane, 0.18 mL of triethyl amine and 139 mg of TBSCl. After 3h, to the mixture was added water. The mixture was extracted withdichloromethane and 30% isopropanol in chloroform. The combined organicfractions were dried with sodium sulfate and concentrated in vacuo. Theresulting residue was dissolved in 5 mL of dichloromethane. To thesolution was added 1 drop of DMF, and 1 mL of oxalyl chloride (2 M indichloromethane) at 0° C. The resulting mixture was warmed to 23° C. andstirred for 30 min before the mixture was concentrated in vacuo. Theresidue was diluted into 5 mL of dichloromethane, and to the solutionwas added 100 mg of methyl 2-aminocyclohex-1-ene-1-carboxylate. Themixture was stirred overnight. The reaction mixture was concentrated,and to the residue was added 20 mL of THF/MeOH/water (3:1:1) and 8 mL ofLiOH (1 N). The mixture was stirred at RT for 8 h and concentrated to asmaller volume. To the residue was added concentrated HCl dropwise untilpH<3. The mixture was extracted with 30% isopropanol in chloroform. Theorganic fraction was concentrated and the residue was purified byRP-HPLC to give Example 24. ¹H NMR (Acetone-d₆, 500 MHz) δ 11.7 (1H, s),8.32 (1H, s), 8.01 (1H, s), 7.78 (1H, d), 7.56 (1H, s), 7.40 (1H, d),2.93 (2H, m), 2.87 (2H, t), 2.63 (2H, t), 2.32 (2H, m), 1.60 (4H, m);LCMS m/z 357 (M+1).

Example 25

The cyanopyridine prepared above, was reduced with DIBAL-H understandard conditions, and the aldehyde (173 mg), in 5 mL of THF and 2 mLof water was combined with hydroxylamine hydrochloride (99 mg). Themixture was stirred for 5 h and concentrated in vacuo. The residue waspurified by Biotage eluting with 5%-20% of ethyl acetate in 1:1 mixtureof dichloromethane and hexane to give the oxime.

To this oxime (50 mg) and 4-pentynoic acid (76 mg) in 10 mL ofdichloromethane at 0° C. was added 0.4 mL of NaOCl (>=4% in water).After 12 h, the solvent was removed, and to the residue was added 6 mLof DMF and 3 mL of NaOCl (>=4% in water). The mixture was stirred at RTfor 2 days. The mixture was filtered, and the filtrate was purified withRP-HPLC to give the isoxazole.

To this PMB ether intermediate (42 mg), was added 1 mL ofdichloromethane and 1 mL of TFA. After 30 min, the mixture wasconcentrated, and to the residue was added 10 mL of dichloromethane, 73uL of triethyl amine and 48 mg of TBSCl. After 3 h, to the mixture wasadded water. The mixture was then extracted with dichloromethane and 30%isopropanol in chloroform. The combined organic fractions were driedwith sodium sulfate and concentrated in vacuo. Following similarprocedures as described in the Examples above, acylation anddeprotection provided Example 25. ¹H NMR (Acetone-d₆, 500 MHz) δ 11.8(1H, s), 8.31 (1H, s), 7.94 (1H, s), 7.39 (1H, d), 6.73 (1H, s), 2.93(2H, t), 2.82 (2H, t), 2.68 (2H, m), 2.33 (2H, m), 1.60 (4H, m); LCMSm/z 358 (M+1).

Example 26

To the commercially available olefin (5 g) in 20 mL of propanol wasadded 0.5 mL of concentrated sulfuric acid. The mixture was heated atreflux for 2 days. The reaction mixture was purified by Biotage (5%ethyl acetate in hexane) to give the propyl ester as a colorless oil.

To a solution of this ester (4.8 g) and NMO (9.9 g) in 30 mL ofdichloromethane was added OsO₄ (4.2 mL, 4% in water). The mixture wasstirred for 12 h at RT. To the resulting solution was added water (150mL) and dichloromethane (300 mL). The organic layer was concentrated. Tothe residue was added acetone (300 mL) and sodium periodate (14.4 g) inwater (80 mL). A white slurry was formed. After 30 min, the slurry wasfiltered, and the filtrate was concentrated in vacuo. The residue waspurified by Biotage (5% ethyl acetate in hexane) to give thecorresponding aldehyde as a colorless oil. To this aldehyde was addedt-butanol (25 mL), 2-methyl-2-butene (15 mL), a mixture of sodiumchlorite (14.5 g, 80%) and sodium dihydrophosphate (18 g) in water (75mL) at 0° C. The resulting brown solution was slowly warmed to 23° C.and stirred for 1.5 h. To this mixture was added NaOH (1 N) until pH=8.The organic layer was removed. To the aqueous layer was addedconcentrated HCl until pH=3. The mixture was then extracted with ethylacetate (200 mL×3). The combined organic layers were dried to give themonoacid as a colorless oil.

To this acid intermediate (1 g) in 10 mL of toluene was added thionylchloride (2 mL) at room temperature. The mixture was heated at 80° C.for 1 h, and the volatiles were removed and azetroped with toluene. Theresidue was then dissolved in pyridine (10 mL), and to the mixture wasadded the N-hydroxy amidine (1.0 g) described in the above Examples. Theresulting mixture was heated at 120° C. for 2 h and then purified byBiotage (5-40% ethyl acetate in hexane) to give the oxadiazole as abrown oil. Following similar procedures described in the Examples above,acylation and deprotection gave the desired Example 26 as a white solid.¹H NMR (DMSO-d₆, 500 MHz) δ 11.6 (1H, s), 10.7 (1H, bs), 8.27 (1H, d),7.90 (1H, d), 7.31 (1H, dd), 2.86 (1H, dd), 2.80 (1H, dd), 2.74 (3H, m),2.22 (2H, m), 1.52 (4H, m), 1.37 (3H, d); LCMS m/z 373 (M+1).

Example 27

The similar procedures as described for the preparation of Example 26above, gave the racemic oxadiazole ester intermediate shown below.

This oxadiazole intermediate (5 g) was purified by chrial AD-H to givetwo enantiomers. To each enantiomer (1.5 g) in 100 mL of THF/MeOH/waterwas added LiOH (15 mL, 1 N) at 0° C. After 30 min at 0° C., the mixturewas acidified with HCl to pH=2-3. After the removal of the organicsolvent in vacuo, the residue was extracted with 30% isopropanol inchloroform. The organic layer was dried with sodium sulfate. The removalof solvent in vacuo gave the acid containing some inorganic salt.

This material was submitted to amide formation following the sameprocedures as described in the Examples above, which was subsequentlytreated with dichloromethane (20 mL), triisopropylsilane (2 mL) andtreated dropwise with TFA (10 mL). The resulting mixture was stirred at0° C. for 25 min, and the mixture was concentrated in vacuo. The residuewas dissolved in DMSO and purified by RP-HPLC to give an enriched singleenantiomer of Example 27 (83% ee determined by chiral OJ-R). The sameprocedure starting with the opposite enantiomer gave enantiomericallyenriched Example 27 (71% ee determined by chrial OJ-R).

These enantiomers of Example 27 were subsequently repurified andresolved by preparative SFC chiral chromatography (ChiralPak AD, 35%methanol(TFA)—CO₂) to obtain each enantiomer at 98-99% ee. Enantiomer A:¹H NMR (DMSO-d₆, 500 MHz) δ 11.7 (1H, s), 10.7 (1H, bs), 8.27 (1H, d),7.88 (1H, d), 7.31 (1H, dd), 3.24 (1H, dd), 3.07 (1H, dd), 3.02 (1H, m),2.75 (2H, m), 2.21 (2H, m), 1.51 (4H, m), 1.27 (3H, d); LCMS m/z 373(M+1). Enantiomer B: ¹H NMR (CD₃OD-d₆, 500 MHz) δ 8.25 (1H, d), 8.05(1H, d), 7.42 (1H, dd), 3.34 (1H, dd), 3.12 (2H, m), 2.87 (2H, m), 2.34(2H, m), 1.62 (4H, m), 1.37 (3H, d); LCMS m/z 373 (M+1).

Example 28

To a preheated (50° C.) slurry of copper (II) chloride (932 mg), 10 mLof acetonitrile was added, along with the thiazole aminoester (1 g) andamyl nitrite (737 mg). The mixture was heated at 50° C. for 2 h. Theresulting mixture was concentrated and purified by Biotage (5-10% ethylacetate in hexane) to give the chloride as a brown solid.

To 4-iodopyrazole (715 mg) in 15 mL of THF was added NaH (161 mg, 60%)at 0° C. After 30 min, to this mixture was added the chlorideintermediate (595 mg). After 30 min at 0° C., the mixture was warmed toRT and stirred for 8 h. The mixture was quenched with water andextracted with ethyl acetate. The organic layer contained some whitesolid which is pure biaryl product, and was collected by filtration. Thefiltrate was concentrated and further purified by Biotage (20-100% ethylacetate in hexane) to give additional biaryl product as a white solid.

To this iodo intermediate (750 mg) in 30 mL of THF was dropwise addediPrMgCl (1.4 mL, 2 M in diethyl ether) at −78° C. under nitrogen to givea light brown solution. After 1 h at −78° C., to the resulting solutionwas added B(OMe)₃ (0.29 mL). The mixture was slowly warmed to 23° C. andstirred for 12 h. The mixture was partitioned between ethyl acetate andwater. The organic layer was concentrated and treated with 10 mL of 30%hydrogen peroxide and 50 mL of THF. The mixture was heated at 50° C. forovernight. The mixture was then concentrated and purified by RP-HPLC togive the hydroxypyrazole.

To this alcohol intermediate (200 mg) was added 15 mL ofdichloromethane, 0.15 mL of triethylamine and 148 mg of TBSCl. The crudemixture was concentrated and purified by Biotage (5-10% ethyl acetate inhexane) to give the silyl ether as an off-white solid.

To this methyl ester (265 mg) in 20 mL of dichloromethane was addedDIBAL-H (5 mL, 1 M in hexane) at −78° C. The mixture was warmed to RTand stirred for 5 h before it was quenched with a saturated solution ofRochelle's salt. The slurry was stirred vigorously, and the aqueouslayer was extracted with dichloromethane. The combined organic layerswere dried with sodium sulfate and concentrated to give thehydroxymethylene product as a crude oil, which was directly used for thenext step.

To this crude alcohol (300 mg) in 10 mL of dichloromethane was addedsodium bicarbonate (121 mg) and Dess-Martin periodinane (490 mg). After2 h, the crude mixture was purified by Biotage (10% ethyl acetate inhexane) to give the aldehyde.

To a solution of trimethyl phosphonate acetate (182 mg) in 20 mL of THFwas added n-butyllithium (0.75 mL, 1.6 M in hexane) at 0° C. Theresulting solution was stirred at this temperature for 30 min. To thissolution was added a THF solution (5 mL) of the aldehyde intermediate(270 mg). The mixture was slowly warmed to RT and stirred for 2 hours.After quenching the mixture with water, the mixture was extracted withethyl acetate, concentrated and purified by Biotage to give the methylenoate as a white solid.

A mixture of methyl enoate (159 mg) and p-toluenesulfonyl hydrazide (2g) in 30 mL of methanol was heated at 65° C. for 2.5 days. The solventwas removed, and the residue was purified by RP-HPLC to give thesaturated methyl ester as a white solid.

To this methyl ester (40 mg) in 5 mL of THF:MeOH:water (3:1:1) was addedLiOH (1.5 mL, 1 M). The mixture was stirred for 2 hours. After beingacidified with concentrated HCl until pH=3, the slurry was extractedwith 30% isopropanol in chloroform, dried with sodium sulfate andconcentrated in vacuo to give the acid as an oily solid.

Following the similar amide formation and hydrolysis proceduresdescribed in the Examples above, Example 28 was obtained as a whitesolid. ¹H NMR (Acetone-d₆, 500 MHz) δ 11.8 (1H, s), 7.84 (1H, s), 7.42(1H, s), 7.27 (1H, s), 3.13 (2H, t), 2.95 (2H, t), 2.71 (2H, t), 2.34(2H, m), 1.62 (4H, m); LCMS m/z 363 (M+1).

Example 29

To a solution of 4-methoxyaniline (1.57 g) in 10% HCl (18 mL) was addedsodium nitrite (0.87 g) in 4 mL of water at 0° C. After being stirred at0° C. for 30 min, to this mixture was added dropwise, a solution ofmethyl isocyanoacetate (1.05 g) and sodium acetate (6.63 g) in methanol(40 mL) and water (12 mL) at 0° C. The mixture was stirred at 0° C. for1.5 h. The solvent was removed in vacuo and the residue was extractedwith ethyl acetate, washed with 5% HCl, saturated sodium bicarbonatesolution and brine. The solution was then dried with sodium sulfate andpurified by Biotage (40-80% ethyl acetate in hexane) to give thetriazole intermediate.

To a solution of this triazole ester (0.7 g) in THF (40 mL) was addedLiBH₄ (79 mg). The mixture was heated under reflux for 1 h and cooled to23° C. The mixture was then quenched with 1 N HCl. After removing thesolvent, the residue was dissolved in ethyl acetate, washed withsaturated sodium bicarbonate solution, brine and dried with sodiumsulfate. The concentration of this mixture gave the hydroxymethyleneintermediate.

To this alcohol (0.46 g) was added 50 mL of dichloromethane andDess-Martin reagent (227 mg) at 0° C. The mixture was warmed to RT andstirred for an additional 3 h. The mixture was purified by Biotage(40-80% ethyl acetate in hexane) to give the aldehyde.

To a solution of trimethyl phosphosphonoacetate (301 mg) in 20 mL of THFwas added n-BuLi (0.73 mL, 2.5 M in hexane) at 0° C. After 30 min, tothis solution was added the aldehyde intermediate (0.30 g). Theresulting solution was stirred at RT for 1 h. To the solution was thenadded dichloromethane/water. The mixture was extracted with 30%isopropanol in chloroform. The organic layer was concentrated andpurified by Biotage (40-80% ethyl acetate in hexane) to give the methylenoate.

A mixture of the methyl enoate intermediate (186 mg), ca. 60 mg Pd/C(10%) and 200 mL of methanol/dichloromethane (1:1) was subjected tohydrogenation under a hydrogen balloon. After 20 min, the reactionmixture was filtered and the filtrate was concentrated to give thesaturated methyl ester as a white solid.

Following the similar amide formation and hydrolysis proceduresdescribed in the Examples above, Example 29 was obtained as a whitesolid. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.5 (1H, bs), 11.7 (1H, s), 9.77(1H, s), 7.57 (2H, d), 6.88 (2H, dd), 2.95 (2H, t), 2.82 (2H, m), 2.72(2H, t), 2.23 (2H, m), 1.53 (4H, m); LCMS m/z 357 (M+1).

Example 30

BuLi (10 mmol, 1.3 eq, 2.5M/THF, 4 mL) was added to a THF (8 mL)solution of trimethyl phosphonoacetate (9.23 mmol, 1.2 eq, 1.68 g) at−78° C. and stirred for 30 min. The solution was warmed to 0° C. for 10min and re-cooled to −78° C. Then a THF (5 mL) solution of4-ethynylbenzaldehyle (7.69 mmol, 1 eq, 1.00 g) was added dropwise andstirred for 2 h at RT. The reaction was partitioned between AcOEt andH₂O. The organic layer was dried, and the residue was recrystallizedwith CH₂Cl₂/MeOH to obtain a light yellow solid product.

A mixture of this methyl enoate acetylide (460 mg, 1 eq, 2.47 mmol), CuI(0.1 eq. 24 mg) and azidotrimethylsilane (427 mg, 1.5 eq, 3.71 mmol)were mixed in DMF/MeOH (5 mL, 9/1) in a sealed tube and heated to 100°C. for 15 h. The reaction solution was cooled to RT and diluted withAcOEt (10 mL). The solution was filtered through celite and dried underreduced pressure. The residue was recrystallized with CH₂Cl₂/MeOH toobtain a light yellow solid product triazole.

Then LiOH (0.5 M, 8 mL) was added to this methyl ester (450 mg, 1.97mmol) in MeOH/THF (10 mL, 1/9) and stirred until all solids weredissolved (about 2 h). Then 20 mL of MeOH was added to this solution,followed by Pd/C (10 mg), and the mixture was subjected to hydrogenationunder balloon pressure for 15 h. The reaction solution was filtered andacidified to pH=7. The product white solid was obtained by filtration ofthe precipitate.

Following the similar amide formation and hydrolysis proceduresdescribed in the Examples above, Example 30 was obtained. ¹H NMR (CD₃OD,500 MHz) δ 8.12 (s, 1H), 7.75 (d, 2H), 7.33 (d, 2H), 3.00 (t, 2H), 2.89(t, 2H), 2.65 (t, 2H), 2.32 (t, 2H), 1.62 (m, 4H); LCMS m/z 339 (M−1).

Example 31

To racemic malic acid (1.03 g) was added 2,2-dimethoxypropane (25 mL)and p-TsOH hydrate (30 mg). The mixture was stirred overnight before theaddition of sodium acetate. The mixture was stirred for additional 3 hand filtered. The filtrate was concentrated, and the mono-protected acidwas crystallized from chloroform/hexane as a white solid.

To a solution of this acid intermediate (281 mg) in 10 mL ofdichloromethane was added CDI (524 mg). The resulting mixture wasstirred for 1 h, and to this mixture was added the N-hydroxy amidine(1.32 g) and dichloromethane (10 mL). The mixture was stirred over 2days and then filtered. The filtrate was concentrated, and the residuewas suspended in toluene (40 mL) and heated to 120° C. for 6 h and 130°C. for 2 h. After removing the solvent, the residue was purified byBiotage (20-40% ethyl acetate in hexane) to give the oxadiazoleintermediate, which was dissolved in chloroform (5 mL) and treated withTFA (2.5 mL) for 20 min. The mixture was concentrated, and to theresidue was added 5% KOH in ethanol (50 ml). The resulting mixture wasstirred for 6 h and acidified with HCl until pH=4. The solution wasextracted with 30% isopropanol in chloroform. The extracts wereconcentrated and purified by RP-HPLC to give the hydroxypyridylalpha-hydroxy acid intermediate. Following similar procedures asdescribed for the Examples above, Example 31 was obtained aftersilylation, amide formation and hydrolysis. ¹H NMR (CD₃OD, 500 MHz) δ8.25 (1H, s), 8.06 (1H, dd), 7.42 (1H, dd), 4.63 (1H, dd), 3.62 (1H, m),3.52 (1H, m), 2.92 (1H, m), 2.35 (1H, m), 1.63 (6H, m); LCMS m/z 375(M+1).

Example 32

A solution of the commercially available olefinic acid shown in Scheme21 (20 g) in ethanol (150 mL) in the presence of 0.5 mL of concentratedsulfuric acid, was heated under reflux for 1 day. A pad of 3 A molecularsieves above the reaction flask was used to absorb the water generatedfrom the reaction. The mixture containing the volatile ester was cooledto 0° C., and to the mixture was added NMO (21.9 g) and 4% of OsO₄ (1mL). The solution was stirred at 0° C. for 1 h and then warmed to 23° C.and stirred overnight. Most of the solvent in this mixture was removedin vacuo, the residue was partitioned between water and ethyl acetate.The organic layer was concentrated to give the diol intermediate as abrown oil.

To a solution of this diol in 300 mL of acetone at 0° C. was added aslurry of sodium periodate (87 g) in 400 mL of water. The resultingwhite slurry was slowly warmed to RT and stirred for 1.5 h. The slurrywas filtered and washed with acetone, and the filtrate was extractedwith dichloromethane. The combined organic layers were carefullyconcentrated to provide the volatile aldehyde as a brown oil. At 0° C.,to the solution of this aldehyde and tert-butanol (150 mL) was added2-methyl-2-butene (20 mL) and a solution of sodium dihydrophosphate (15g) and sodium chlorite (41 g, ˜80%). The resulting brown mixture wasslowly warmed to RT, and the mixture was stirred for 5 h. To the mixturewas added 10% sodium hydroxide until pH>11. The mixture was then washedwith ethyl acetate, and the aqueous layer was acidified withconcentrated HCl until pH=4. The resulting aqueous fraction wasextracted with ethyl acetate. The combined organic fractions were driedwith sodium sulfate and concentrated in vacuo to give the mono-acidmono-ester as a colorless oil.

To a solution of this acid intermediate (13.5 g) in 120 mL ofdichloromethane were added 50 μL of DMF and 97 mL of oxalyl chloride (2M in dichloromethane) at 0° C. The mixture was stirred at 0° C. for 30min, warmed to 23° C., and the resulting solution was stirred for anadditional 2 h. After removing the volatiles, to the residue was addedthe N-hydroxy amidine (21.2 g) and 100 mL of pyridine. The mixture wasthen heated at 130° C. for overnight. The pyridine was removed in vacuo,and the residue was partitioned between water and dichloromethane. Theorganic phase was concentrated and purified by Biotage (eluting with10-40% ethyl acetate in hexane) to give the bi-heterocyclic intermediateas a white solid.

To this ester (15.1 g) in 400 mL of THF/MeOH/water (3:1:1), was addedLiOH (200 mL, 1 N) dropwise. The mixture was stirred at room temperaturefor 2 h. After removing most organic solvent in vacuo, the aqueous layerwas acidified with 1 N HCl to pH=3. The precipitate was extracted withdichloromethane thrice. The combined organic phase was dried with sodiumsulfate and concentrated to give the acid as a white solid.

To a solution of this acid intermediate (14.3 g) in 300 mL ofdichloromethane, were added N-hydroxysuccinimide (4.52 g) and EDCI (7.53g). The mixture was stirred for 2.5 h and then diluted to 1 L ofdichloromethane. The resulting solution was washed with brine and driedwith sodium sulfate. The solution was concentrated, and the resultingresidue was dissolved in 700 mL of dioxane. To this solution was addedammonia in water (60 mL, 28-30%) at 0° C. The resulting mixture wasstirred at RT for 15 min. The volatiles were removed in vacuo, and theresidue was partitioned between water and dichloromethane. The organicphase was washed with water, saturated sodium bicarbonate, and thendried with sodium sulfate. The resulting solution was concentrated togive the primary carboxamide as a white solid.

A mixture of this carboxamide (6.83 g), the enol triflate (12.9 g),Pd₂(dba)₃ (1.31 g), Cs₂CO₃ (9.9 g, anhydrous), Xantphos (2.48 g) and 200mL of dioxane was heated under argon at 80° C. for overnight. Themixture was cooled and filtered through celite, concentrated, andpurified by Biotage (20-40% ethyl acetate in hexane) to give thecyclohexenylamide ester as an oil.

To this ester (8.6 g) in 84 mL of dichloromethane was addedtriisopropylsilane (8.4 mL) and TFA (40 mL) at 0° C. The mixture wasstirred at room temperature for 15 min, the solvents removed, theresidue dissolved in 200 mL of THF/MeOH/water (3:1:1), and the mixturetreated dropwise with excess of LiOH (1 N). The mixture was stirred atRT overnight, and after removing most organic solvents in vacuo, theaqueous layer was washed with ethyl acetate. The aqueous layer was thenacidified with 1N HCl to pH=5. The precipitate was collected byfiltration, washed with water and diethyl ether to give the product as acrude material. This material was dissolved in 30% isopropanol inchloroform and filtered. The filtrate was concentrated to a small volumeand the homogeneous mixture was kept at 0° C. overnight. The precipitatewas collected, washed with methanol, then diethyl ether and dried undervacuum to provide Example 32 as a white solid. ¹H NMR (Acetone-d6, 500MHz) δ 12.1 (1H, s), 8.36 (1H, s), 7.98 (1H, d), 7.41 (1H, d), 3.27 (2H,s), 2.95 (2H, m), 2.37 (2H, m), 1.63 (4H, m), 1.46 (6H, s); LCMS m/z 387(M+1).

Example 33

To (S)-pulegone (4 g) was added concentrated HCl (3.8 mL) and 12 mL ofwater. The mixture was heated at reflux for 20 h under vigorousstirring. The mixture was distilled to remove acetone and the heatingoil was heated at 180° C. to distill off both organic layer and HCl(aq). The organic layer was separated from the aqueous layer and thenwas diluted with diethyl ether and washed with sodium bicarbonatesolution. The organic layer was then dried with sodium sulfate andconcentrated carefully to remove most of the diethyl ether to give the(S)-3-methylcyclohexanone.

To this (S)-3-methylcyclohexanone (2 g) in 50 mL of THF, was addedLiHMDS (20 mL, 1 M in THF) at −78° C. The mixture was slowly warmed to0° C. and stirred for 30 min before the solution was re-cooled to −78°C. To this mixture was added methyl cyanoformate (1.55 mL), and themixture was stirred at −20° C. for 2 h before the addition of 1 N HClsolution. The aqueous layer was extracted with diethyl ether andpurified by Biotage (10-20% diethyl ether in hexane) to give theketoester as a colorless oil.

To this ketoester intermediate (1 g) in 20 mL of methanol, was addedammonium acetate (4.6 g), and the mixture was stirred overnight. Afterthe removal of the solvent, the residue was diluted with ethyl acetate.The solid was filtered off, and the filtrate was washed with water,brine and dried with sodium sulfate. The liquid was then concentrated togive the (S)-cyclohexene aminoester as an oily solid.

The enantiomeric ester intermediates from Example 27 above (200 mg) wereeach heated at 70° C. in 1 mL of concentrated HCl/HOAc (v:v=1:2) for 30min. The resulting mixture was concentrated under high vacuum overnight.The enantiomeric acids were then submitted directly for the nextamidation step with the (S)-cyclohexene aminoester as described in theExamples above.

Following the similar hydrolysis procedures as described in the Examplesabove, provided two of the four possible diasteromers of Example 33containing minor epimerization. (S)-Diastereomer A: ¹H NMR (DMSO-d₆, 500MHz) δ 12.6 (1H, s), 11.7 (1H, s), 10.6 (1H, s), 8.26 (1H, s), 7.88 (1H,d), 7.30 (1H, d), 3.02 (4H, m), 2.33 (2H, m), 2.16 (1H, m), 1.60 (2H,m), 1.27 (3H, s), 1.09 (1H, m), 0.91 (3H, d); LCMS m/z 387 (M+1).(S)-Diastereomer B: ¹H NMR (DMSO-d₆, 500 MHz) δ 12.6 (1H, s), 11.69 (1H,s), 10.6 (1H, s), 8.26 (1H, s), 7.88 (1H, d), 7.30 (1H, d), 3.02 (4H,m), 2.33 (2H, m), 2.16 (1H, m), 1.60 (2H, m), 1.27 (3H, s), 1.09 (1H,m), 0.91 (3H, d); LCMS m/z 387 (M+1).

Utilizing the commercially available (R)-3-methylcyclohexanone, providedaccess to the additional other two diastereomers of Example 33. Thus toa suspension of sodium hydride (3.57 g, 89.15 mmol, 60% dispersion inoil) in anhydrous dioxane (25 mL) was added dimethyl carbonate (30 mL,356.6 mmol). The resulting mixture was heated to 85° C., and a solutionof (R)-3-methylcyclohexanone (5.0 g, 44.64 mmol) in dioxane (50 mL) wasadded dropwise via an addition funnel. After stirring at 80° C. for 2hours, the reaction mixture was cooled to room temperature and quenchedwith 1N HCl. The resulting mixture was concentrated, the residue wasextracted with ether, and the organic layer was washed with brine, driedover magnesium sulfate, filtered and concentrated. The residue waspurified by Biotage using a gradient of 0-5% ethyl acetate-hexanes togive the desired product as a white crystalline solid.

To a solution of this methyl ketoester intermediate (2.5 g, 14.7 mmol)in methanol (50 mL) was added ammonium acetate (5.66 g, 73.52 mmol). Thereaction mixture was left stirring at RT for 16 h. It was thenconcentrated, and the residue was diluted with ethyl acetate and washedwith water. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. A white solid wasobtained for this methyl (R)-cyclohexene aminoester intermediate.

As before, the enantiomeric ester intermediates from Example 27 abovewere each converted to their respective acids. One enantiomeric acid wasthen submitted directly for the next amidation step with the methyl(R)-cyclohexene aminoester as described in the Examples above. Followingthe similar hydrolysis procedures as described in the Examples above,and subsequent purification by reverse phase HPLC, provided the thirddiastereomer of Example 33 containing minor epimerization.(R)-Diastereomer A: ¹H NMR (500 MHz, DMSO-d₆) δ 11.73 (s, 1H), 8.26 (s,1H), 7.9 (d, 1H), 7.37 (dd, 1H), 3.26 (m, 1H), 3.0 (m, 3H), 2.4 (m, 2H),2.1 (m, 1H), 1.6 (m, 2H), 1.28 (d, 3H), 1.08 (m, 1H), 0.93 (d, 3H); LCMSm/z 387 (M+1).

To obtain the fourth diastereomer of Example 33, a solution of the(R)-3-methyl cyclohexanone (2.18 g, 19.46 mmol) in anhydrous THF (50mL), cooled to −78° C., was treated with LiHMDS (23.35 mL, 1.0 M inTHF). After 15 minutes, benzyl cyanoformate was added. The reactionmixture was slowly warmed to 0° C. over an hour, and quenched by theaddition of 1N HCl. The resulting mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified byBiotage SP—I using a gradient of 0-15% ethyl acetate-hexanes to give thedesired product as a colorless oil.

To a solution of this benzyl ketoester intermediate (1.0 g, 4.06 mmol)in methanol (20 mL) was added ammonium acetate (1.57 g, 20.32 mmol).After stirring the reaction at 23° C. for 16 hours it was concentrated.The residue was diluted with ethyl acetate and washed with water. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. A white solid was obtained for thisbenzyl (R)-cyclohexene aminoester intermediate.

As before, the enantiomeric ester intermediates from Example 27 abovewere each converted to their respective acids. One enantiomeric acid wasthen submitted directly for the next amidation step with the benzyl(R)-cyclohexene aminoester as described in the Examples above. Followingthe similar PMB-ether deprotection procedures as described in theExamples above, provided the benzyl ester penultimate intermediate.

To a solution of this benzyl ester intermediate (27 mg, 0.056 mmol) inmethanol (2 mL) was added Pd/C (10 mg). The resulting solution wasstirred under a hydrogen balloon for 15 minutes. The reaction mixturewas filtered through celite. The filtrate was concentrated and purifiedby reverse phase HPLC to provide the fourth diastereomer of Example 33containing minor epimerization. (R)-Diastereomer B: ¹H NMR (500 MHz,DMSO-d₆) δ 11.69 (s, 1H), 8.26 (s, 1H), 7.88 (d, 1H), 7.3 (dd, 1H), 3.24(m, 1H), 3.0 (m, 3H), 2.4 (m, 2H), 2.1 (m, 1H), 1.6 (m, 2H), 1.26 (d,3H), 1.1 (m, 1H), 0.92 (d, 3H); LCMS m/z 387 (M+1).

Example 34

The enantiomers of Example 34 were generated from the respective methyl(R)-cyclohexene aminoester and methyl (S)-cyclohexene aminoesterintermediates prepared in Example 33 above. These enantiomeric methylcyclohexene aminoesters were acylated with the requisite carboxylic acidintermediate from Example 23, and the amides converted to the desiredproducts following the procedures described in the Examples above.(S)-Enantiomer: ¹H NMR (CD₃OD, 500 MHz) δ 8.23 (1H, s), 8.01 (1H, d),7.34 (1H, d), 3.29 (2H, m), 3.08 (1H, bd), 2.99 (2H, bs), 2.50 (1H, bd),2.41 (1H, m), 2.28 (1H, m), 1.70 (1H, m), 1.66 (1H, m), 1.18 (1H, m),1.01 (3H, d); LCMS m/z 373 (M+1). (R)-Enantiomer: ¹H NMR (500 MHz,DMSO-d₆) δ 11.66 (s, 1H), 8.26 (s, 1H), 7.91 (d, 1H), 7.32 (dd, 1H), 3.2(t, 2H), 3.0 (dd, 1H), 2.9 (m, 2H), 2.4 (m, 2H), 2.1 (m, 1H), 1.6 (m,2H), 1.15 (m, 1H), 0.95 (d, 3H); LCMS m/z 373 (M+1).

Example 35

Commercially available 4-ethylcyclohexanone was converted to its methylketoester via Mander's reagent under the conditions described in theExamples above. This material as an orange oil was used in the next stepwithout any further purification.

To a solution of this methyl ketoester intermediate (475 mg, 2.6 mmol)in anhydrous THF (25 mL) cooled to 0° C., was added NaH (113 mg, 2.84mmol, 60%). After 30 min,2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (1.13 g, 2.84mmol) was added, and the resulting reaction stirred at room temperaturefor 2 h. The reaction mixture was quenched with 1N HCl, then extractedwith EtOAc. The organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to give a brown oil. This material waspurified by Biotage using 50% EtOAc/hexanes as eluant to give thedesired enol triflate intermediate.

As shown in Scheme 23, the methyl ester intermediate from Example 23 canbe directly converted to its primary carboxamide. Thus to a solution ofthis methyl ester in dioxane in a pressure tube was added 7N ammonia inmethanol. The resulting solution was heated at 70° C. for 16 hours. Thereaction mixture was cooled to room temperature and concentrated to givethe desired primary carboxamide intermediate as a white solid.

To a solution of the enol triflate intermediate (150 mg, 0.37 9 mmol) inanhydrous dioxane (3 mL) was added the primary carboxamide intermediate(112 mg, 0.316 mmol), XANTPHOS (37 mg, 0.06 mmol), cesium carbonate (46mg, 0.36 mmol) and Pd₂(dba)₃ (20 mg, 0.019 mmol). The resulting mixturewas de-gassed for 2 minutes by bubbling N₂. The reaction was heated at60° C. under a N₂ atmosphere for 18 h. The reaction mixture was cooledto RT, and filtered through celite. The filtrate was concentrated, andthe residue was purified by Prep-TLC (30% ethyl acetate-hexanes) to givethe desired amide product.

To a solution of this intermediate (89 mg, 0.171 mmol) in DCM (2 mL) wasadded triisopropyl silane (0.3 mL) followed by TFA (1 mL). Afterstirring the mixture for 20 min, it was cooled to 0° C. and carefullyquenched by the addition of saturated sodium bicarbonate solution. Theresulting mixture was extracted with 30% isopropanol/chloroform. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. This material was dissolved in THF (5 mL), 1N NaOH (2 mL)was added followed by enough MeOH to obtain a homogenous solution. Afterstirring the reaction at room temperature for 18 h, it was neutralizedwith 1N HCl. The resulting mixture was extracted with 20%isopropanol/chloroform. The organic layer was washed with brine anddried over Na₂SO₄, filtered and concentrated. The residue was purifiedby reverse phase HPLC (10-100% acetonitrile/H₂O (1% TFA)) to provideExample 35. ¹H NMR (CD₃OD, 500 MHz), δ 8.25 (d, 1H), 7.90-7.88 (d, 1H)7.31-7.29 (dd, 1H), 3.18 (t, 2H), 2.99-2.88 (m, 3H), 2.69-2.63 (m, 1H),2.44-2.40 (m, 1H), 1.78-1.73 (m, 2H), 1.30-1.23 (m, 3H), 1.10-1.06 (m,1H), 0.866 (t, 3H); LCMS m/z 387 (M+1).

Example 36

To a solution of 3-(trifluoromethyl)-phenol (3.0 g, 18.51 mmol) inmethanol (20 mL) was added Rh/Al₂O₃ (100 mg). The resulting mixture wasstirred under hydrogen atmosphere (50 psi) for 16 h. The reaction wasfiltered through celite and concentrated to give the cyclohexanol as acolorless oil.

To a solution of this cyclohexanol intermediate (3.0 g, 17.85 mmol) indichloromethane (100 mL) was added Dess-Martin reagent (9.0 g, 21.42mmol). After stirring at room temperature for 4 h, the mixture wasquenched with saturated sodium bicarbonate solution. The resultingmixture was extracted with dichloromethane. The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated to give theketone as a colorless oil.

To a solution of this cyclohexanone intermediate (2.0 g, 12.04 mmol) inanhydrous THF cooled to −78° C. was added LiHMDS (14.5 mL, 14.5 mmol,1.0 M in THF). The resulting mixture was warmed to 0° C. and stirred for20 min. The reaction mixture was cooled back to −78° C. and methylcyanoformate (1.15 mL, 14.46 mmol) was added. The reaction mixture waswarmed to −20° C. and quenched with 1N HCl. The resulting mixture wasextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography using 10% ethylacetate-hexanes to give the ketoester as a colorless oil.

To this ketoester intermediate (860 mg, 3.83 mmol) in methanol was addedammonium acetate (1.48 g, 19.2 mmol). After stirring the mixture at roomtemperature for 16 h, it was concentrated. The residue was diluted withethyl acetate and washed with water. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated. Awhite solid of the trifluorocyclohexene aminoester was obtained.

As shown in Scheme 24, the carboxylic acid intermediate from Example 23can be used to acylate this trifluorocyclohexene aminoester. Thus to asolution of the carboxylic acid (100 mg, 0.281 mmol) in anhydrousdichloromethane (5 mL) cooled to 0° C. under nitrogen atmosphere, wasadded DMF (10 μL) followed by oxalyl chloride (0.562 mL, 2.0 M solutionin DCM). The reaction mixture was warmed to 23° C. and stirred for 30min. The reaction mixture was concentrated, and the residue wasdissolved in anhydrous dichloromethane. A solution of thetrifluorocyclohexene aminoester (140 mg, 0.627 mmol) in dichloromethane(2 mL) was added. After stirring the mixture at RT for 16 h, it wasquenched by the addition of saturated sodium bicarbonate solution. Theresulting mixture was extracted with dichloromethane. The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography using 40% ethylacetate-hexanes to give the desired amide methyl ester as a white solid.

To a solution of this ester intermediate (44 mg) in THF (2 mL) was added0.5 N NaOH (2 mL), followed by MeOH (1 mL). After stirring the mixturefor 1 h, it was quenched by neutralizing with 1N HCl (1 mL). Theresulting mixture was concentrated, and the residue was diluted withwater (5 mL) and extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by reverse phase HPLC to provide Example 36. ¹H NMR(500 MHz, DMSO-d₆) δ 11.64 (s, 1H), 10.62 (bs, 1H), 8.26 (bs, 1H), 7.9(d, 1H), 7.32 (dd, 1H), 3.2 (m, 3H), 2.9 (m, 2H), 2.75 (m, 1H), 2.6 (m,2H), 2.2 (m, 1H), 1.9 (m, 1H), 1.4 (m, 1H); LCMS m/z 427 (M+1).

Example 37

To a suspension of copper(I) iodide (3.8 g, 20 mmol) in anhydrous ether(20 mL) cooled to 0° C. under a nitrogen atmosphere was added dropwise asolution of methyl lithium (25 mL, 40 mmol, 1.6 M in diethylether).After stirring the mixture at 0° C. for 20 min, it was cooled to −78° C.and 3-methyl 2-cyclohexen-1-one was added. The reaction mixture wasslowly warmed to −20° C. over 1 h and quenched by the addition of conc.ammonium hydroxide solution (10 mL). The resulting biphasic solution wasstirred for 20 min. The aqueous layer was extracted with ether, and theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography using 10% ethyl acetate-hexanes to give the desiredgeminal dimethyl cyclohexanone as a yellow oil.

To a solution of this cyclohexanone intermediate (740 mg, 5.86 mmol) inanhydrous THF (20 mL) cooled to −78° C. under a nitrogen atmosphere, wasadded LiHMDS (7 mL, 7 mmol, 1.0 M solution). After 15 min, methylcyanoformate (0.558 mL, 7.03 mmol) was added. After stirring the mixtureat −78° C. for 20 min, it was quenched with 1N HCl. The biphasic mixturewas extracted with ethyl acetate, washed with brine and dried overanhydrous sodium sulfate. The organic layer was filtered, concentratedand purified by flash chromatography using 10% ethyl acetate hexanes togive the ketoester as a colorless oil.

To a solution of this ketoester intermediate (500 mg, 2.72 mmol) inmethanol (30 mL) was added ammonium acetate (1.05 g, 13.6 mmol). Afterstirring the reaction mixture at room temperature for 48 h, it wasconcentrated, and the residue was diluted with ethyl acetate and washedwith water. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. A white solid wasobtained for the geminal dimethyl cyclohexene aminoester intermediate.

As shown in Scheme 25, the carboxylic acid intermediate from Example 23can be used to acylate this cyclohexene aminoester. Thus to a solutionof the carboxylic acid (100 mg, 0.281 mmol) in methylene chloride (4 mL)and DMF (20 uL), was added oxalyl chloride (0.281 mL, 0.563 mmol) at 0°C. The solution was stirred at RT for 30 min, then concentrated. To theresulting residue was added methylene chloride (3 mL) followed by asolution of the cyclohexene aminoester intermediate (129 mg, 0.703 mmol)in methylene chloride (2 mL). The reaction was stirred at 23° C. underN₂ for 3 h, then quenched with saturated NaHCO₃ solution and extractedwith methylene chloride. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified on silica, eluting with a gradient of 20%-60% EtOAc/hexanesover 10 column volumes, then 60%-100% EtOAc/hexanes over 4 columnvolumes, affording the desired amide as a white solid.

To a solution of this PMB ether intermediate (84 mg, 0.161 mmol) inmethylene chloride (4 mL) was added triisopropylsilane (500 uL, 2.441mmol) then TFA (2 ml, 26.0 mmol). The reaction was stirred for 5 min,then slowly quenched at 0° C. with saturated aqueous NaHCO₃ in an icebath. This mixture was extracted with methylene chloride then 30%IPA/CHCl₃. The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The solid residue was used in thenext step without further purification.

To this ester intermediate was added THF (2 mL), NaOH (2 mL, 1.0 mmol)and methanol (1 mL). The mixture was stirred overnight, then quenchedwith 1N HCl (1 mL) and concentrated. The mixture was diluted with waterand extracted with EtOAc. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated to an oily residue.The residue was purified by reverse phase HPLC to provide Example 37. ¹HNMR (500 MHz, DMSO-d₆) δ 11.67 (s, 1H), 8.26 (d, 1H), 7.89 (d, 1H), 7.30(dd, 1H), 3.18 (t, 2H), 2.90 (t, 2H), 2.59 (s, 2H), 2.25 (t, 2H), 1.29(t, 2H), 0.87 (s, 6H); LCMS m/z 369 (M−17).

Example 38

To a suspension of 5-amino-2-cyano pyridine (20.0 g, 0.168 mol) inHF-pyridine (100 g) in an Erlenmeyer flask cooled to 0° C. was addedsodium nitrite (17.4 g, 0.251 mol) in four portions. After 45 min at 0°C. the reaction mixture was stirred at room temperature for 30 min andthen heated to 80° C. for 90 min. The reaction mixture was quenched bypouring into ice/water mixture. The resulting mixture was extracted withDCM. The organic layer was dried over anhydrous sodium sulfate, filteredand concentrated to give the fluoropyridine as an orange solid.

To a suspension of this fluoropyridine nitrile intermediate (16.0 g,0.131 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.157mmol, 50% by wt). After stirring the reaction at room temperature for 48h, it was filtered through a fritted funnel. The precipitate was washedwith ether and dried under vacuum to give the N-hydroxy amidine as ayellow solid.

To a suspension of this amidine intermediate (5.32 g, 34.32 mmol) inanhydrous pyridine (10 mL) was added 4-chloro-4-oxo-methyl butyrate (5mL, 41.18 mmol). The resulting reaction mixture was heated at 120° C.for 2 h. The mixture was cooled to RT and concentrated. The residue wasdissolved in ethyl acetate and washed with 1N HCl, water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to give a dark brown solid. This material was purified byBiotage using 25%-60% ethyl acetate-hexanes gradient to give theheterobiaryl intermediate as a light yellow solid.

To a solution of this ester intermediate (900 mg, 3.58 mmol) in THF (4mL) was added methanol (2 mL) followed by 5N NaOH (1 mL). After 30 min,the reaction mixture was neutralized by the addition of 1N HCl (5 mL).The reaction mixture was concentrated. The residue was extracted withethyl acetate, and the organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to give a lightyellow solid of the carboxylic acid.

To a solution of this acid intermediate (50 mg, 0.21 mmol) in anhydrousdichloromethane (4 mL) cooled to 0° C. under nitrogen atmosphere wasadded DMF (10 μL) followed by oxalyl chloride (0.21 mL, 2.0 M solutionin DCM). The reaction was warmed to 23° C. and stirred for 30 min. Thereaction mixture was concentrated, and the residue was dissolved inanhydrous dichloromethane (2 mL) and cooled to 0° C. A dichloromethane(2 mL) solution of the methyl (R)-cyclohexene aminoester described inthe Examples above (90 mg, 0.525 mmol) was then added. The ice-bath wasremoved, and the resulting solution was stirred at RT for 16 h. Thereaction mixture was quenched by the addition of saturated sodiumbicarbonate solution. The resulting mixture was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography using 25% then 35% ethyl acetate-hexanes to give theamide as a white solid.

To a solution of this amide ester intermediate (41 mg) in THF was added1N LiOH (1 mL). The resulting mixture was stirred for 16 h. The reactionmixture was neutralized by the addition of 1N HCl (1 mL). The resultingbiphasic mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by reverse phase HPLC to provide Example 38 as the(R)-enantiomer. ¹H NMR (500 MHz, DMSO-d₆) δ 12.6 (bs, 1H), 11.64 (s,1H), 8.76 (d, 1H), 8.14 (dd, 1H), 7.93 (dt, 1H), 3.2 (t, 2H), 2.9 (m,3H), 2.3 (m, 2H), 2.15 (m, 1H), 1.6 (m, 2H), 1.1 (m, 1H), 0.92 (d, 3H);LCMS m/z 397 (M+Na).

Example 39

To a solution of 3-hydroxy benzaldehyde (1.2 g, 10 mmol) in anhydrousDCM (50 mL) was added imidazole (1.02 g, 15 mmol) followed by TBSCl(1.65 g, 11 mmol). After stirring the reaction at room temperature for 1h, it was quenched by pouring into saturated sodium bicarbonatesolution. The resulting mixture was extracted with DCM, and the organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto give the silyl ether aldehyde.

To a solution of this aldehyde intermediate (2.24 g, 9.5 mmol) inethanol (50 mL) was added sodium borohydride (0.5 g, 14.5 mmol). Afterstirring the mixture at RT for 1 h, it was concentrated, and the residuewas dissolved in ethyl acetate and washed with water and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to give the hydroxy methylene intermediate.

To a solution of this alcohol (2.25 g, 9.5 mmol) in anhydrous THF (50mL) cooled to 0° C. under a nitrogen atmosphere was added sodium hydride(0.57 g, 14.25 mmol). After 15 min, methyl iodide (0.89 mL, 14.25 mmol)was added. After stirring the mixture at room temperature for 1 h, itwas quenched with saturated ammonium chloride solution. The resultingmixture was extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude materialwas dissolved in THF (20 mL) and TBAF (2 mL) was added. After 1 h, thereaction mixture was concentrated and the residue purified by flashchromatography using 30% ethyl acetate hexanes to give the methyl etheras a colorless oil.

To a solution of this phenol intermediate (0.9 g, 6.52 mmol) in methanol(20 mL) was added Rh/Al₂O₃ (50 mg). The resulting mixture was stirredunder a hydrogen balloon for 18 h. The mixture was filtered throughcelite and concentrated to give the desired cyclohexanol as a colorlessoil.

To a solution of this cyclohexanol (870 mg, 6 mmol) in DCM cooled to−78° C. was added DMSO (0.85 ml, 12 mmol) followed by oxalyl chloride(4.5 mL, 2M in DCM). After 10 min, triethylamine (1.67 mL, 12 mmol) wasadded and the reaction mixture slowly warmed to 0° C. over 1 h. Themixture was quenched by pouring into saturated sodium bicarbonatesolution. The resulting mixture was extracted with DCM. The organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography using 10%ethyl acetate-hexanes to give the cyclohexanone intermediate.

To a suspension of sodium hydride (0.225 g, 5.62 mmol, 60% dispersion inoil) in anhydrous dioxane (5 mL) was added dimethyl carbonate (1 mL,11.87 mmol). The resulting mixture was heated to 85° C., and a solutionthe cyclohexanone intermediate (400 mg, 2.81 mmol) in dioxane (5 mL) wasadded dropwise via an addition funnel. After stirring at 80° C. for 2 h,the reaction mixture was cooled to room temperature and quenched with 1NHCl. The resulting mixture was concentrated. The residue was extractedwith ether. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedby flash chromatography 30% ethyl acetate-hexanes to give the ketoester.

To a solution of this ketoester (199 mg, 0.994 mmol) in methanol (12mL), was added ammonium acetate (383 mg, 4.97 mmol). The reaction wasleft stirring at room temperature, and concentrated. The residue wasdissolved in EtOAc and washed with water and brine. The organic phasewas dried over anhydrous sodium sulfate, filtered and concentrated togive the methoxymethyl ether substituted cyclohexene aminoester.

Following similar procedures as described for the Examples above,Example 39 was obtained after amide formation and hydrolysis. Theresidue was purified by reverse phase HPLC to provide Example 39. ¹H NMR(500 MHz, DMSO-d₆) δ 11.66 (s, 1H), 8.76 (d, 1H), 8.14 (dd, 1H), 7.94(m, 1), 3.24-3.20 (m, 7H), 3.01-2.89 (m, 3H), 2.43 (t, 1H), 2.37 (d,1H), 2.16 (m, 1H), 1.75 (m, 1H), 1.68 (br d, 1H), 1.14 (m, 1H); LCMS m/z403 (M−1).

Example 40

To a solution of tetrahydro-4-H-pyran-4-one (1 mL, 10.82 mmol) inanhydrous THF (50 mL) cooled to −78° C. under a nitrogen atmosphere, wasadded lithium diisopropylamide (6.5 mL, 13.02 mmol, 2.0 M solution).After 20 min, methyl cyanoformate (1.03 mL, 13.03 mmol) was added. Theresulting mixture was slowly warmed to −20° C., and quenched withsaturated ammonium chloride solution. The biphasic mixture was extractedwith ethyl acetate, washed with brine and dried over anhydrous sodiumsulfate. The organic layer was filtered, concentrated and purified byflash chromatography using 30% ethyl acetate hexanes to give theketoester as a colorless oil.

To a solution of this ketoester intermediate (0.450 g, 2.85 mmol) inanhydrous THF (20 mL) cooled to 0° C., was added sodium hydride (0.171g, 4.27 mmol, 60% by weight). After 30 min,2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (1.34 g, 3.42mmol) was added. After stirring the reaction mixture at room temperaturefor 2 h, it was quenched with saturated ammonium chloride solution. Theresulting mixture was extracted with ethyl acetate, and the combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography using 30% ethyl acetate-hexanes to give the enol triflateas colorless oil.

To a solution of 6-methoxy-2-naphthaldehyde (3.72 g, 20.0 mmol) intoluene (40 mL) placed in a pressure vessel, was addedmethyl(triphenylphosphoranylidene)acetate (6.7 g, 20 mmol). Theresulting mixture was refluxed at 120° C. for 18 h. The reaction mixturewas concentrated and purified using a Biotage flash 40M column with 15%ethyl acetate-hexanes as the eluant, to provide the enoate.

To a solution of this enoate (4.64 g, 19.14 mmol) in 1:1dichloromethane-methanol (100 mL) was added Pd/C. The resulting mixturewas stirred under a H₂ balloon for 18 h. The reaction mixture wasfiltered through celite and concentrated to give the methoxy ester as awhite solid.

To a solution of this methyl ether intermediate (3.0 g, 12.3 mmol) inDCM (80 mL) cooled to 0° C., was added BBr₃ (61.5 mL, 1.0M in DCM).After 30 min, the mixture was quenched with methanol (50 mL) followed bycold water. The resulting mixture was concentrated, and the residuediluted with water and extracted with dichloromethane. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated. Thisnaphtholic ester was used in the next step without any furtherpurification.

To a solution of this ester intermediate (3.0 g, 12.3 mmol) in1,4-dioxane (50 mL) placed in a pressure tube, was added concentratedNH₄OH solution. The resulting mixture was stirred at RT for 18 h. Thereaction mixture was concentrated and the residue was suspended in ethylacetate, washed with water, dried over anhydrous sodium sulfate filteredand concentrated. The residue was purified by flash chromatography using50% ethyl acetate-hexanes then 100% ethyl acetate as the eluant to givethe naphtholic primary carboxamide as an off-white solid.

To a solution of the enol triflate intermediate (100 mg, 0.344 mmol) inanhydrous dioxane (3 mL) was added the primary carboxamide intermediate(61 mg, 0.287 mmol), XANTPHOS (40 mg, 0.068 mmol), cesium carbonate (157mg, 0.481 mmol) and Pd₂(dba)₃ (19 mg, 0.02 mmol). The resulting mixturewas degassed for 2 min by bubbling N₂ gas. The reaction mixture washeated at 50° C. under a N₂ atmosphere for 2 h. The reaction mixture wascooled to room temperature, and filtered through celite. The filtratewas concentrated and purified by flash chromatography using 40% ethylacetate-hexanes to give the amide product.

To a solution of this ester penultimate intermediate (44 mg) in THF (2mL) was added 1N NaOH (1 mL) followed by MeOH (1 mL). The resultingmixture was stirred at 23° C. for 5 h. The reaction mixture was quenchedby the addition of 1N HCl (1 mL). The resulting mixture wasconcentrated, and the residue was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified byreverse phase HPLC (Gilson) to provide Example 40. ¹H NMR (500 MHz,DMSO-d₆) δ 11.38 (s, 1H), 9.59 (bs, 1H), 7.65 (d, 1H), 7.56 (m, 2H),7.28 (d, 1H), 7.05 (m, 2H), 4.16 (s, 2H), 3.65 (t, 2H), 2.9 (t, 2H),2.86 (bt, 2H), 2.65 (t, 2H); LCMS m/z 342 (M+1).

Example 41

Potassium hexamethyldisilazide (35 mL of a 0.5 M solution in THF, 17.5mmol) was added to propyl triphenylphosphonium bromide (7.1 g, 18.5mmol) in toluene (75 mL) at 0° C. The solution was stirred for 15 min,and the ketone (2.1 g, 12.3 mmol) in toluene (50 mL) was added. Thesolution was stirred at 0° C. for 1 h and then heated at 100° C.overnight. Solvent was removed, and the product was purified by flashchromatography (Biotage, Horizon) 0 to 10% ethyl acetate/hexanes. Theproduct was dissolved in methanol (150 mL) and stirred over palladium oncarbon (5%, 1 g) under an atmosphere of hydrogen overnight. The solutionwas filtered through celite and solvent was removed. The product wasdissolved in THF/MeOH/3N HCl (50 mL/20 mL/10 mL) for 36 h. The mixturewas neutralized with saturated sodium bicarbonate, and the solvent wasremoved. The solution was washed with ethyl acetate, and the resultingorganic layer was washed with brine and dried over Na₂SO₄. The productwas purified by flash chromatography (Biotage, Horizon) 0 to 20% ethylacetate/hexanes.

To a solution of the ketone (796 m g, 5.2 mmol) in anhydrous THF (25 mL)cooled to −78° C. under a N₂ atmosphere, was added LiHMDS (6.2 mL, 6.2mmol, 1.0 M in THF). After 30 min, methyl cyanoformate (0.538 mL, 6.7mmol) was added, and the reaction mixture was allowed to warm to 0° C.over several hours. The mixture was quenched with 1N HCl and extractedwith EtOAc (2×). The organic layer was washed with brine and dried overNa₂SO₄, filtered and concentrated in vacuo. This material was used inthe next step without any further purification.

To a solution of the ketoester (1095 mg, 5.2 mmol) in anhydrous THF (50mL) was added NaH (309 mg, 7.7 mmol, 60%). After 15 min,2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (2.02 g, 5.2mmol) was added. The reaction mixture was stirred at room temperaturefor 18 h and then quenched with water. The resulting mixture wasextracted with EtOAc (2×). The organic layer was washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was purified by flash chromatography (Biotage, Horizon) (0%EtOAc/Hexane to 20% EtOAc/Hexane) to give the desired product.

To a solution of the vinyl triflate (200 mg, 0.58 mmol) in anhydrousdioxane (11 mL) was added the amide (15 mg, 0.07 mmol), XANTPHOS (32 mg,0.05 mmol), cesium carbonate (22 mg, 0.17 mmol) and Pd₂(dba)₃ (20 mg,0.02 mmol). The resulting mixture was de-gassed for 2 min by bubblinggaseous N₂. The mixture was heated at 60° C. under a N₂ atmosphere for18 h. The reaction mixture was cooled to room temperature, and filteredthrough celite. The filtrate was concentrated in vacuo, and the residuewas purified by reverse phase HPLC (Gilson) to give the desired product.

To a solution of the methyl ester in dioxane (3 mL) was added MeOH (1mL) and 1N LiOH (1 mL). The resulting mixture was stirred at roomtemperature for 18 h, and then neutralized to pH=7 by the addition of 1NHCl, and purified by reverse phase HPLC (Gilson) to provide Example 41.¹H NMR (500 MHz, DMSO-d₆) δ 7.65 (d, 1H), 7.58 (d, 1H), 7.56 (s, 1H),7.28 (d, 1H), 7.06-7.02 (m, 2H), 2.97-2.88 (m, 3H), 2.65-2.63 (m, 3H),2.45-2.33 (m, 2H), 1.84-1.71 (m, 1H), 1.65-1.62 (m, 1H), 1.51-1.15 (m,4H), 0.901 (d, 3H), 0.86 (t, 3H); LCMS m/z 396 (M+1).

Biological Assays

The activity of the compounds of the present invention regarding niacinreceptor affinity and function can be evaluated using the followingassays:

³H-Niacin Binding Assay:

1. Membrane: Membrane preps are stored in liquid nitrogen in:

-   -   20 mM HEPES, pH 7.4    -   0.1 mM EDTA

Thaw receptor membranes quickly and place on ice. Resuspend by pipettingup and down vigorously, pool all tubes, and mix well. Use clean human at15 μg/well, clean mouse at 10 ug/well, dirty preps at 30 ug/well.

-   -   1a. (human): Dilute in Binding Buffer.    -   1b. (human+4% serum): Add 5.7% of 100% human serum stock (stored        at −20° C.) for a final concentration of 4%. Dilute in Binding        Buffer.    -   1c. (mouse): Dilute in Binding Buffer.        2. Wash buffer and dilution buffer: Make 10 liters of ice-cold        Binding Buffer:    -   20 mM HEPES, pH 7.4    -   1 mM MgCl₂    -   0.01% CHAPS (w/v)    -   use molecular grade or ddH₂O water        3. [5,6-³H]-nicotinic acid: American Radiolabeled Chemicals,        Inc. (cat # ART-689). Stock is ˜50 Ci/mmol, 1 mCi/ml, 1 ml total        in ethanol→20 μM

Make an intermediate ³H-niacin working solution containing 7.5% EtOH and0.25 μM tracer. 40 μL of this will be diluted into 200 μL total in eachwell→1.5% EtOH, 50 nM tracer final.

4. Unlabeled nicotinic acid:

-   -   Make 100 mM, 10 mM, and 80 μM stocks; store at −20° C. Dilute in        DMSO.

5. Preparing Plates:

-   -   1) Aliquot manually into plates. All compounds are tested in        duplicate. 10 mM unlabeled nicotinic acid must be included as a        sample compound in each experiment.    -   2) Dilute the 10 mM compounds across the plate in 1:5 dilutions        (8 μl:40 μl).    -   3) Add 195 μL binding buffer to all wells of Intermediate Plates        to create working solutions (250 μM→0). There will be one        Intermediate Plate for each Drug Plate.    -   4) Transfer 5 μL from Drug Plate to the Intermediate Plate. Mix        4-5 times.

6. Procedure:

-   -   1) Add 140 μL of appropriate diluted 19CD membrane to every        well. There will be three plates for each drug plate: one human,        one human+serum, one mouse.    -   2) Add 20 μL of compound from the appropriate intermediate plate    -   3) Add 40 μL of 0.25 μM ³H-nicotinic acid to all wells.    -   4) Seal plates, cover with aluminum foil, and shake at RT for        3-4 hours, speed 2, titer plate shaker.    -   5) Filter and wash with 8×200 μL ice-cold binding buffer. Be        sure to rinse the apparatus with >1 liter of water after last        plate.    -   6) Air dry overnight in hood (prop plate up so that air can flow        through).    -   7) Seal the back of the plate    -   8) Add 40 μL Microscint-20 to each well.    -   9) Seal tops with sealer.    -   10) Count in Packard Topcount scintillation counter.    -   11) Upload data to calculation program, and also plot raw counts        in Prism, determining that the graphs generated, and the IC₅₀        values agree.

The compounds of the invention generally have an IC₅₀ in the³H-nicotinic acid competition binding assay within the range of 1 nM toabout 25 μM.

³⁵S-GTPγS binding assay:

Membranes prepared from Chinese Hamster Ovary (CHO)—K1 cells stablyexpressing the niacin receptor or vector control (7 μg/assay) werediluted in assay buffer (100 mM HEPES, 100 mM NaCl and 10 mM MgCl₂, pH7.4) in Wallac Scintistrip plates and pre-incubated with test compoundsdiluted in assay buffer containing 40 μM GDP (final [GDP] was 10 μM) for˜10 minutes before addition of ³⁵S-GTPγS to 0.3 nM. To avoid potentialcompound precipitation, all compounds were first prepared in 100% DMSOand then diluted with assay buffer resulting in a final concentration of3% DMSO in the assay. Binding was allowed to proceed for one hour beforecentrifuging the plates at 4000 rpm for 15 minutes at room temperatureand subsequent counting in a TopCount scintillation counter. Non-linearregression analysis of the binding curves was performed in GraphPadPrism.

Membrane Preparation Materials:

CHO—K1 cell culture medium: F-12 Kaighn's Modified Cell Culture Mediumwith 10% FBS, 2 mM L-Glutamine, 1 mM Sodium Pyruvate and 400 μ{tildeover (g)}/ml G418

-   Membrane Scrape Buffer: 20 mM HEPES-    10 mM EDTA, pH 7.4-   Membrane Wash Buffer: 20 mM HEPES-    0.1 mM EDTA, pH 7.4-   Protease Inhibitor Cocktail: P-8340, (Sigma, St. Louis, Mo.)

Procedure:

(Keep everything on ice throughout prep; buffers and plates of cells)

-   -   Aspirate cell culture media off the 15 cm² plates, rinse with 5        mL cold PBS and aspirate.    -   Add 5 ml Membrane Scrape Buffer and scrape cells. Transfer        scrape into 50 mL centrifuge tube. Add 50 uL Protease Inhibitor        Cocktail.    -   Spin at 20,000 rpm for 17 minutes at 4° C.    -   Aspirate off the supernatant and resuspend pellet in 30 mL        Membrane Wash Buffer. Add 50 μL Protease Inhibitor Cocktail.    -   Spin at 20,000 rpm for 17 minutes at 4° C.    -   Aspirate the supernatant off the membrane pellet. The pellet may        be frozen at −80° C. for later use or it can be used        immediately.

Assay Materials:

-   Guanosine 5′-diphosphate sodium salt (GDP, Sigma-Aldrich Catalog    #87127)-   Guanosine 5′-[γ³⁵S] thiotriphosphate, triethylammonium salt    ([³⁵S]GTPγS, Amersham Biosciences Catalog #SJ1320, ˜1000 Ci/mmol)-   96 well Scintiplates (Perkin-Elmer #1450-501)-   Binding Buffer: 20 mM HEPES, pH 7.4-    100 mM NaCl-    10 mM MgCl₂-   GDP Buffer: binding buffer plus GDP, ranging from 0.4 to 40 μM, make    fresh before assay

Procedure:

-   -   (total assay volume=100 {tilde over (μ)}well)    -   25 μL GDP buffer with or without compounds (final GDP 10 μM—so        use 40 μM stock)    -   50 μL membrane in binding buffer (0.4 mg protein/mL)    -   25 μL [³⁵S]GTPγS in binding buffer. This is made by adding 5 μl        [³⁵S]GTPγS stock into 10 mL binding buffer (This buffer has no        GDP)    -   Thaw compound plates to be screened (daughter plates with 5 μL        compound @ 2 mM in 100% DMSO)    -   Dilute the 2 mM compounds 1:50 with 245 μL GDP buffer to 40 μM        in 2% DMSO. (Note: the concentration of GDP in the GDP buffer        depends on the receptor and should be optimized to obtain        maximal signal to noise; 40 μM).    -   Thaw frozen membrane pellet on ice. (Note: they are really        membranes at this point, the cells were broken in the hypotonic        buffer without any salt during the membrane prep step, and most        cellular proteins were washed away)    -   Homogenize membranes briefly (few seconds—don't allow the        membranes to warm up, so keep on ice between bursts of        homogenization) until in suspension using a POLYTRON PT3100        (probe PT-DA 3007/2 at setting of 7000 rpm). Determine the        membrane protein concentration by Bradford assay. Dilute        membrane to a protein concentrations of 0.40 mg/ml in Binding        Buffer. (Note: the final assay concentration is 20 μg/well).    -   Add 25 μL compounds in GDP buffer per well to Scintiplate.    -   Add 50 μL of membranes per well to Scintiplate.        -   Pre-incubate for 5-10 minutes at room temperature. (cover            plates with foil since compounds may be light sensitive)    -   Add 25 μL of diluted [³⁵S]GTPγS. Incubate on shaker (Lab-Line        model #1314, shake at setting of 4) for 60 minutes at room        temperature. Cover the plates with foil since some compounds        might be light sensitive.    -   Assay is stopped by spinning plates sealed with plate covers at        2500 rpm for 20 minutes at 22° C.    -   Read on TopCount NXT scintillation counter—35S protocol.

The compounds of the invention generally have an EC₅₀ in the functionalin vitro GTPγS binding assay within the range of about less than 1 μM toas high as about 100 μM.

Flushing Via Laser Doppler

Male C57B16 mice (˜25 g) are anesthetized using 10 mg/ml/kg Nembutalsodium. When antagonists are to be administered they are co-injectedwith the Nembutal anesthesia. After ten minutes the animal is placedunder the laser and the ear is folded back to expose the ventral side.The laser is positioned in the center of the ear and focused to anintensity of 8.4-9.0 V (with is generally ˜4.5 cm above the ear). Dataacquisition is initiated with a 15 by 15 image format, auto interval, 60images and a 20 sec time delay with a medium resolution. Test compoundsare administered following the 10th image via injection into theperitoneal space. Images 1-10 are considered the animal's baseline anddata is normalized to an average of the baseline mean intensities.

Materials and Methods—Laser Doppler Pirimed PimII; Niacin (Sigma);Nembutal (Abbott labs).

All patents, patent applications and publications that are cited hereinare hereby incorporated by reference in their entirety. While certainpreferred embodiments have been described herein in detail, numerousalternative embodiments are seen as falling within the scope of theinvention.

1-28. (canceled)
 29. A method of treating atherosclerosis,dyslipidemias, diabetes, metabolic syndrome or a related condition in ahuman patient in need of such treatment, comprising administering to thepatient a therapeutically effective amount of a compound represented byformula I:

or a pharmaceutically acceptable salt or solvate thereof is disclosedwherein: X represents CH₂, O, S, S(O), SO₂ or NH, such that when Xrepresents NH, the nitrogen atom may be optionally substituted with R⁶,C(O)R⁶, or SO₂R⁶, wherein: R⁶ represents C₁₋₃alkyl optionallysubstituted with 1-3 groups, 0-3 of which are halo, and 0-1 of which areselected from the group consisting of: OC₁₋₃alkyl, OH, NH₂, NHC₁₋₃alkyl,N(C₁₋₃alkyl)₂, CN, Hetcy, Aryl and HAR, said Aryl and HAR being furtheroptionally substituted with 1-3 groups, 1-3 of which are halo, and 0-1of which are selected from the group consisting of: OH, NH₂, C₁₋₃alkyl,C₁₋₃alkoxy, haloC₁₋₃alkyl and haloC₁₋₃alkoxy groups; a and b are eachintegers 1, 2 or 3, such that the sum of a and b is 2, 3 or 4; ring Arepresents a 6-10 membered aryl, a 5-13 membered heteroaryl or apartially aromatic heterocyclic group, said heteroaryl and partiallyaromatic heterocyclic group containing at least one heteroatom selectedfrom O, S, S(O), S(O)₂ and N, and optionally containing 1 otherheteroatom selected from O and S, and optionally containing 1-3additional N atoms, with up to 5 heteroatoms being present; each R² andR³ is independently H, C₁₋₃alkyl, haloC₁₋₃alkyl, OC₁₋₃alkyl,haloC₁₋₃alkoxy, OH or F; n represents an integer of from 1 to 5; each R⁴is H or is independently selected from halo and R⁶; R⁵ represents —CO₂H,

or —C(O)NHSO₂R^(e) wherein R^(e) represents C₁₋₄alkyl or phenyl, saidC₁₋₄alkyl and phenyl each being optionally substituted with 1-3 groups,1-3 of which are selected from halo and C₁₋₃alkyl, and 1-2 of which areselected from the group consisting of: OC₁₋₃alkyl, haloC₁₋₃alkyl,haloC₁₋₃alkoxy, OH, NH₂ and NHC₁₋₃alkyl; and each R¹ is H or isindependently selected from the group consisting of: a) halo, OH, CO₂H,CN, NH₂, S(O)₀₋₂R^(e), C(O)R^(e), OC(O)R^(e) and CO₂R^(e), wherein R^(e)is as previously defined; b) C₁₋₆ alkyl and OC₁₋₆alkyl, said C₁₋₆alkyland alkyl portion of OC₁₋₆alkyl being optionally substituted with 1-3groups, 1-3 of which are halo and 1-2 of which are selected from: OH,CO₂H, CO₂C₁₋₄alkyl, CO₂C₁₋₄haloalkyl, OCO₂C₁₋₄alkyl, NH₂, NHC₁₋₄alkyl,N(C₁₋₄alkyl)₂, Hetcy and CN; c) NHC₁₋₄alkyl and N(C₁₋₄alkyl)₂, the alkylportions of which are optionally substituted as set forth in (b) above;d) C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂, C(O)Hetcy,C(O)NHOC₁₋₄alkyl and C(O)N(C₁₋₄alkyl)(OC₁₋₄alkyl), the alkyl portions ofwhich are optionally substituted as set forth in (b) above; e)NR′C(O)R″, NR′SO₂R″, NR′CO₂R″ and NR′C(O)NR″R′″ wherein: R′ representsH, C₁₋₃alkyl or haloC₁₋₃alkyl, R″ represents (a) C₁₋₈alkyl optionallysubstituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which areselected from the group consisting of: OC₁₋₆alkyl, OH, CO₂H,CO₂C₁₋₄alkyl, CO₂C₁₋₄haloalkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂, CN,Hetcy, Aryl and HAR, said Hetcy, Aryl and HAR being further optionallysubstituted with 1-3 halo, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl orhaloC₁₋₄alkoxy groups; or (b) Hetcy, Aryl or HAR, each being optionallysubstituted with 1-3 members selected from the group consisting of:halo, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl and haloC₁₋₄alkoxy groups;and R′″ representing H or R″; f) phenyl or a 5-6 membered heteroaryl ora Hetcy group attached at any available ring atom and each beingoptionally substituted with 1-3 groups, 1-3 of which are selected fromhalo, C₁₋₃alkyl and haloC₁₋₃alkyl groups, and 1-2 of which are selectedfrom OC₁₋₃alkyl and haloOC₁₋₃alkyl groups, and 0-1 of which is selectedfrom the group consisting of: i) OH; CO₂H; CN; NH₂ and S(O)₀₋₂R^(e)wherein R^(e) is as described above; ii) NHC₁₋₄alkyl and N(C₁₋₄alkyl)₂,the alkyl portions of which are optionally substituted with 1-3 groups,1-3 of which are halo and 1-2 of which are selected from: OH, CO₂H,CO₂C₁₋₄alkyl, CO₂C₁₋₄haloalkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂ and CN;iii) C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂, C(O)NHOC₁₋₄alkyl andC(O)N(C₁₋₄alkyl)(OC₁₋₄alkyl), the alkyl portions of which are optionallysubstituted as set forth in b) above; and iv) NR′C(O)R″, NR′SO₂R″,NR′CO₂R″ and NR′C(O)NR″R′″ wherein R′, R″ and R′″ are as describedabove.
 30. The method of claim 29, comprising administering to thepatient a compound of Formula I in an amount that is effective fortreating atherosclerosis.
 31. The method of claim 29, comprisingadministering to the patient a compound of Formula I in an amount thatis effective for treating dyslipidemias.
 32. The method of claim 29,comprising administering to the patient a compound of Formula I in anamount that is effective for treating diabetes.
 33. The method of claim29, comprising administering to the patient a compound of Formula I inan amount that is effective for treating metabolic syndrome.
 34. Themethod of treating atherosclerosis, dyslipidemias, diabetes, metabolicsyndrome or a related condition, in accordance with claim 29, in a humanpatient in need of such treatment, comprising administering to thepatient a compound of Formula I and a DP receptor antagonist, saidcompounds being administered in an amount that is effective to treatatherosclerosis, dyslipidemia, diabetes or a related condition in theabsence of substantial flushing.
 35. The method in accordance with claim34 wherein the DP receptor antagonist selected from the group consistingof compounds A through AJ:

or a pharmaceutically acceptable salt or solvate thereof.
 36. A methodof treating atherosclerosis, dyslipidemias, diabetes, metabolic syndromeor a related condition in a human patient in need of such treatment,comprising administering to the patient a therapeutically effectiveamount of a compound selected from: TABLE 1

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

Compound 41

or a pharmaceutically acceptable salt or solvate thereof.
 37. The methodof claim 36, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.